|
Inhibition of PI3Kalpha using 1-alpha-phosphatidylinositol as substrate by ATP depletion assay
|
None
|
30.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Antiproliferative activity against human A2780 cells after 3 days by CellTiter-Glo assay
|
Homo sapiens
|
520.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3K-mediated AKT Ser473 phosphorylation in human A2780 cells after 1 hr
|
Homo sapiens
|
55.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3K p110alpha subunit using [gamma33P]ATP by filter binding assay
|
None
|
52.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3K p110alpha H1047R mutant using [gamma33P]ATP by filter binding assay
|
Homo sapiens
|
58.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3K p110alpha E545K mutant using [gamma33P]ATP by filter binding assay
|
Homo sapiens
|
99.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3K p110beta subunit using [gamma33P]ATP by filter binding assay
|
None
|
166.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3K p110delta subunit using [gamma33P]ATP by filter binding assay
|
None
|
116.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3K p110gamma subunit using [gamma33P]ATP by filter binding assay
|
None
|
262.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3K-mediated AKT Ser473 phosphorylation in PTEN-deficient human A2780 cells after 1 hr
|
Homo sapiens
|
74.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3K-mediated AKT Ser473 phosphorylation in PTEN-deficient human U87MG cells after 1 hr
|
Homo sapiens
|
130.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3Kalpha E545K mutant-mediated AKT Ser473 phosphorylation in human MCF7 cells after 1 hr
|
Homo sapiens
|
100.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3K-mediated AKT Ser473 phosphorylation in human DU145 cells harboring LKB1 mutation after 1 hr
|
Homo sapiens
|
73.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3K-mediated AKT Ser473 phosphorylation in human A2780 cells xenografted in nu/nu mouse at 60 mg/kg, po after 10 hrs by immunoblotting
|
Mus musculus
|
90.0
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3K-mediated AKT Ser473 phosphorylation in human A2780 cells xenografted in nu/nu mouse at 100 mg/kg, po after 10 hrs by immunoblotting
|
Mus musculus
|
90.0
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
Year : 2011
Volume : 2
Issue : 10
First Page : 774
Last Page : 779
Authors : Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF.
Abstract : Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
|
Inhibition of PI3Kalpha (unknown origin)
|
Homo sapiens
|
30.0
nM
|
|
Journal : MedChemComm
Title : Small molecules targeting phosphoinositide 3-kinases
Year : 2012
Volume : 3
Issue : 11
First Page : 1337
Last Page : 1355
Authors : Wu P, Hu Y
|
Antiproliferative activity against human HCT116 cells assessed as inhibitory ratio at 10 uM after 72 hrs by MTT assay
|
Homo sapiens
|
89.5
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and antiproliferative activity evaluation of m-(4-morpholinyl-1,3,5-triazin-2-yl)benzamides in vitro.
Year : 2015
Volume : 25
Issue : 8
First Page : 1730
Last Page : 1735
Authors : Wang XM, Xu J, Xin MH, Lu SM, Zhang SQ.
Abstract : In the present study, a series of m-(4-morpholino-1,3,5-triazin-2-yl)benzamides were designed, synthesized and characterized. Their antiproliferative activities against HCT-116 cell and MCF-7 cell at 10μM were evaluated by MTT assay. Compounds T6, T10, T11, T12 and T19 exhibited potent antiproliferative activities. Thus, their IC50 values against HCT-116 cell, MCF-7 cell, Hela cell, U-87 MG cell and A549 cell were measured. The SAR of the target compounds was preliminary discussed. The Western bolt assay suggested that compound T11 can block the PI3K/Akt/mTOR pathway. Hoechst staining assay indicated that compound T11 can cause morphological changes and induce apoptosis of HCT-116 cells. These findings directly identify the m-(4-morpholinyl-1,3,5-triazin-2-yl)benzamide derivatives as novel antiproliferative agents and further verify the value of the benzamide fragment in drug design.
|
Antiproliferative activity against human MCF7 cells assessed as inhibitory ratio at 10 uM after 72 hrs by MTT assay
|
Homo sapiens
|
84.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and antiproliferative activity evaluation of m-(4-morpholinyl-1,3,5-triazin-2-yl)benzamides in vitro.
Year : 2015
Volume : 25
Issue : 8
First Page : 1730
Last Page : 1735
Authors : Wang XM, Xu J, Xin MH, Lu SM, Zhang SQ.
Abstract : In the present study, a series of m-(4-morpholino-1,3,5-triazin-2-yl)benzamides were designed, synthesized and characterized. Their antiproliferative activities against HCT-116 cell and MCF-7 cell at 10μM were evaluated by MTT assay. Compounds T6, T10, T11, T12 and T19 exhibited potent antiproliferative activities. Thus, their IC50 values against HCT-116 cell, MCF-7 cell, Hela cell, U-87 MG cell and A549 cell were measured. The SAR of the target compounds was preliminary discussed. The Western bolt assay suggested that compound T11 can block the PI3K/Akt/mTOR pathway. Hoechst staining assay indicated that compound T11 can cause morphological changes and induce apoptosis of HCT-116 cells. These findings directly identify the m-(4-morpholinyl-1,3,5-triazin-2-yl)benzamide derivatives as novel antiproliferative agents and further verify the value of the benzamide fragment in drug design.
|
Antiproliferative activity against human HCT116 cells after 72 hrs by MTT assay
|
Homo sapiens
|
480.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and antiproliferative activity evaluation of m-(4-morpholinyl-1,3,5-triazin-2-yl)benzamides in vitro.
Year : 2015
Volume : 25
Issue : 8
First Page : 1730
Last Page : 1735
Authors : Wang XM, Xu J, Xin MH, Lu SM, Zhang SQ.
Abstract : In the present study, a series of m-(4-morpholino-1,3,5-triazin-2-yl)benzamides were designed, synthesized and characterized. Their antiproliferative activities against HCT-116 cell and MCF-7 cell at 10μM were evaluated by MTT assay. Compounds T6, T10, T11, T12 and T19 exhibited potent antiproliferative activities. Thus, their IC50 values against HCT-116 cell, MCF-7 cell, Hela cell, U-87 MG cell and A549 cell were measured. The SAR of the target compounds was preliminary discussed. The Western bolt assay suggested that compound T11 can block the PI3K/Akt/mTOR pathway. Hoechst staining assay indicated that compound T11 can cause morphological changes and induce apoptosis of HCT-116 cells. These findings directly identify the m-(4-morpholinyl-1,3,5-triazin-2-yl)benzamide derivatives as novel antiproliferative agents and further verify the value of the benzamide fragment in drug design.
|
Inhibition of PI3Kalpha (unknown origin)
|
Homo sapiens
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and antiproliferative activity evaluation of m-(4-morpholinyl-1,3,5-triazin-2-yl)benzamides in vitro.
Year : 2015
Volume : 25
Issue : 8
First Page : 1730
Last Page : 1735
Authors : Wang XM, Xu J, Xin MH, Lu SM, Zhang SQ.
Abstract : In the present study, a series of m-(4-morpholino-1,3,5-triazin-2-yl)benzamides were designed, synthesized and characterized. Their antiproliferative activities against HCT-116 cell and MCF-7 cell at 10μM were evaluated by MTT assay. Compounds T6, T10, T11, T12 and T19 exhibited potent antiproliferative activities. Thus, their IC50 values against HCT-116 cell, MCF-7 cell, Hela cell, U-87 MG cell and A549 cell were measured. The SAR of the target compounds was preliminary discussed. The Western bolt assay suggested that compound T11 can block the PI3K/Akt/mTOR pathway. Hoechst staining assay indicated that compound T11 can cause morphological changes and induce apoptosis of HCT-116 cells. These findings directly identify the m-(4-morpholinyl-1,3,5-triazin-2-yl)benzamide derivatives as novel antiproliferative agents and further verify the value of the benzamide fragment in drug design.
|
Inhibition of PI3Kalpha (unknown origin)
|
Homo sapiens
|
30.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antitumor activities evaluation of m-(4-morpholinoquinazolin-2-yl)benzamides in vitro and in vivo.
Year : 2015
Volume : 96
First Page : 382
Last Page : 395
Authors : Wang XM, Xin MH, Xu J, Kang BR, Li Y, Lu SM, Zhang SQ.
Abstract : In the present study, a series of m-(4-morpholinoquinazolin-2-yl)benzamides were designed, synthesized and characterized. The antiproliferative activities of the synthesized compounds were evaluated against two human cell lines (HCT-116 and MCF-7). Compounds with IC50 values below 4 μM were further evaluated against U-87 MG and A549 cell lines. Among these evaluated compounds, compound T10 displayed a remarkable antiproliferative effect in vitro. The hoechst staining assay showed that compound T10 caused morphological changes. The cell cycle and apoptosis assay further indicated that compound T10 can arrest HCT-116 cells in G2/M and G0/G1 phase and induce apoptosis. PI3K enzyme assays indicated that compounds T7 and T10 selectively inhibit PI3Kα. A Western bolt assay further suggested that compound T10 can block the PI3K/Akt/mTOR pathway. Moreover, compound T10 inhibited tumor growth on a mice S180 homograft model. These findings directly identify m-(4-morpholinoquinazolin-2-yl)benzamide derivatives as novel anticancer agents.
|
Binding affinity to human PI3Kalpha (R108 to N1068 residues) expressed in mammalian expression system by Kinomescan assay
|
Homo sapiens
|
3.5
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Binding affinity to human PI3Kbeta (P118 to S1070 residues) expressed in mammalian expression system by Kinomescan assay
|
Homo sapiens
|
36.0
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Binding affinity to human PI3Kgamma (S144 to A1102 residues) expressed in mammalian expression system by Kinomescan assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Binding affinity to human PI3Kdelta (R108 to Q1044 residues) expressed in mammalian expression system by Kinomescan assay
|
Homo sapiens
|
260.0
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Binding affinity to human mTOR (L1382 to W2549 residues) expressed in mammalian expression system at 10 uM
|
Homo sapiens
|
19.0
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Binding affinity to human VPS34 (S282 to H879 residues) expressed in mammalian expression system by Kinomescan assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Inhibition of PI3Kalpha (unknown origin)
|
Homo sapiens
|
45.0
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Inhibition of PI3Kbeta (unknown origin)
|
Homo sapiens
|
607.0
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Inhibition of PI3Kgamma (unknown origin)
|
Homo sapiens
|
778.0
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Inhibition of PI3Kdelta (unknown origin)
|
Homo sapiens
|
110.0
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Inhibition of mTOR (unknown origin)
|
Homo sapiens
|
94.0
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Inhibition of PI3Kalpha E542K mutant (unknown origin)
|
Homo sapiens
|
111.0
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Inhibition of PI3Kalpha E545K mutant (unknown origin)
|
Homo sapiens
|
216.0
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Inhibition of PI3Kalpha H2047R mutant (unknown origin)
|
Homo sapiens
|
87.0
nM
|
|
Journal : J Med Chem
Title : 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Year : 2017
Volume : 60
Issue : 17
First Page : 7524
Last Page : 7538
Authors : Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP.
Abstract : Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
|
Inhibition of recombinant human full length N-terminal His-tagged p110alpha/p85alpha expressed in baculovirus expression system using PIP2 as substrate measured after 1 hr by Alexa633 Tracer-based fluorescence polarization assay
|
Homo sapiens
|
40.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines.
Year : 2018
Volume : 9
Issue : 7
First Page : 719
Last Page : 724
Authors : Shen S, He X, Yang Z, Zhang L, Liu Y, Zhang Z, Wang W, Liu W, Li Y, Huang D, Sun K, Ni X, Yang X, Chu X, Cui Y, Lv Q, Lan J, Zhou F.
Abstract : The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.
|
Inhibition of PI3K in human PC3 cells assessed as reduction in AKT phosphorylation at Ser473 measured after 2 hrs by fluorescence assay
|
Homo sapiens
|
365.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines.
Year : 2018
Volume : 9
Issue : 7
First Page : 719
Last Page : 724
Authors : Shen S, He X, Yang Z, Zhang L, Liu Y, Zhang Z, Wang W, Liu W, Li Y, Huang D, Sun K, Ni X, Yang X, Chu X, Cui Y, Lv Q, Lan J, Zhou F.
Abstract : The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.
|
Antiproliferative activity against human T47D cells harboring PI3KCA H1047R mutant after 72 hrs by MTT assay
|
Homo sapiens
|
286.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines.
Year : 2018
Volume : 9
Issue : 7
First Page : 719
Last Page : 724
Authors : Shen S, He X, Yang Z, Zhang L, Liu Y, Zhang Z, Wang W, Liu W, Li Y, Huang D, Sun K, Ni X, Yang X, Chu X, Cui Y, Lv Q, Lan J, Zhou F.
Abstract : The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.
|
Antiproliferative activity against human MCF7 cells harboring PIK3CA E545K mutant after 72 hrs by MTT assay
|
Homo sapiens
|
206.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines.
Year : 2018
Volume : 9
Issue : 7
First Page : 719
Last Page : 724
Authors : Shen S, He X, Yang Z, Zhang L, Liu Y, Zhang Z, Wang W, Liu W, Li Y, Huang D, Sun K, Ni X, Yang X, Chu X, Cui Y, Lv Q, Lan J, Zhou F.
Abstract : The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.
|
Inhibition of recombinant human full-length N-terminal His6-tagged p110beta/recombinant human full length p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate measured after 1 hr by Alexa633 Tracer-based fluorescence polarization assay
|
Homo sapiens
|
234.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines.
Year : 2018
Volume : 9
Issue : 7
First Page : 719
Last Page : 724
Authors : Shen S, He X, Yang Z, Zhang L, Liu Y, Zhang Z, Wang W, Liu W, Li Y, Huang D, Sun K, Ni X, Yang X, Chu X, Cui Y, Lv Q, Lan J, Zhou F.
Abstract : The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.
|
Inhibition of recombinant human full-length His-tagged p110gamma expressed in baculovirus expression system using PIP2 as substrate measured after 1 hr by Alexa633 Tracer-based fluorescence polarization assay
|
Homo sapiens
|
372.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines.
Year : 2018
Volume : 9
Issue : 7
First Page : 719
Last Page : 724
Authors : Shen S, He X, Yang Z, Zhang L, Liu Y, Zhang Z, Wang W, Liu W, Li Y, Huang D, Sun K, Ni X, Yang X, Chu X, Cui Y, Lv Q, Lan J, Zhou F.
Abstract : The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.
|
Inhibition of recombinant human full-length N-terminal His6-tagged p110delta/recombinant human full length p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate measured after 1 hr by Alexa633 Tracer-based fluorescence polarization assay
|
Homo sapiens
|
125.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines.
Year : 2018
Volume : 9
Issue : 7
First Page : 719
Last Page : 724
Authors : Shen S, He X, Yang Z, Zhang L, Liu Y, Zhang Z, Wang W, Liu W, Li Y, Huang D, Sun K, Ni X, Yang X, Chu X, Cui Y, Lv Q, Lan J, Zhou F.
Abstract : The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.
|
Cytotoxicity against HUVEC after 72 hrs by MTT assay
|
Homo sapiens
|
886.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines.
Year : 2018
Volume : 9
Issue : 7
First Page : 719
Last Page : 724
Authors : Shen S, He X, Yang Z, Zhang L, Liu Y, Zhang Z, Wang W, Liu W, Li Y, Huang D, Sun K, Ni X, Yang X, Chu X, Cui Y, Lv Q, Lan J, Zhou F.
Abstract : The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.
|
Inhibition of recombinant human His-tagged p85alpha/p110alpha E542K mutant expressed in insect cells
|
Homo sapiens
|
29.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines.
Year : 2018
Volume : 9
Issue : 7
First Page : 719
Last Page : 724
Authors : Shen S, He X, Yang Z, Zhang L, Liu Y, Zhang Z, Wang W, Liu W, Li Y, Huang D, Sun K, Ni X, Yang X, Chu X, Cui Y, Lv Q, Lan J, Zhou F.
Abstract : The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.
|
Inhibition of recombinant human His-tagged p85alpha/p110alpha E545K mutant expressed in insect cells
|
Homo sapiens
|
11.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines.
Year : 2018
Volume : 9
Issue : 7
First Page : 719
Last Page : 724
Authors : Shen S, He X, Yang Z, Zhang L, Liu Y, Zhang Z, Wang W, Liu W, Li Y, Huang D, Sun K, Ni X, Yang X, Chu X, Cui Y, Lv Q, Lan J, Zhou F.
Abstract : The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.
|
Inhibition of p110alpha H1047R mutant (unknown origin)
|
Homo sapiens
|
25.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines.
Year : 2018
Volume : 9
Issue : 7
First Page : 719
Last Page : 724
Authors : Shen S, He X, Yang Z, Zhang L, Liu Y, Zhang Z, Wang W, Liu W, Li Y, Huang D, Sun K, Ni X, Yang X, Chu X, Cui Y, Lv Q, Lan J, Zhou F.
Abstract : The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.
|
Inhibition of TORC2 in human A2058 cells assessed as decrease in PKB/Akt phosphorylation at Ser473 after 1 hr by Western blot analysis
|
Homo sapiens
|
416.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders.
Year : 2018
Volume : 61
Issue : 22
First Page : 10084
Last Page : 10105
Authors : Rageot D, Bohnacker T, Melone A, Langlois JB, Borsari C, Hillmann P, Sele AM, Beaufils F, Zvelebil M, Hebeisen P, Löscher W, Burke J, Fabbro D, Wymann MP.
Abstract : Mechanistic target of rapamycin (mTOR) promotes cell proliferation, growth, and survival and is overactivated in many tumors and central nervous system disorders. PQR620 (3) is a novel, potent, selective, and brain penetrable inhibitor of mTORC1/2 kinase. PQR620 (3) showed excellent selectivity for mTOR over PI3K and protein kinases and efficiently prevented cancer cell growth in a 66 cancer cell line panel. In C57BL/6J and Sprague-Dawley mice, maximum concentration ( Cmax) in plasma and brain was reached after 30 min, with a half-life ( t1/2) > 5 h. In an ovarian carcinoma mouse xenograft model (OVCAR-3), daily dosing of PQR620 (3) inhibited tumor growth significantly. Moreover, PQR620 (3) attenuated epileptic seizures in a tuberous sclerosis complex (TSC) mouse model. In conclusion, PQR620 (3) inhibits mTOR kinase potently and selectively, shows antitumor effects in vitro and in vivo, and promises advantages in CNS indications due to its brain/plasma distribution ratio.
|
Inhibition of TORC1 in human A2058 cells assessed as decrease in S6 phosphorylation at Ser235/236 after 1 hr by Western blot analysis
|
Homo sapiens
|
553.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders.
Year : 2018
Volume : 61
Issue : 22
First Page : 10084
Last Page : 10105
Authors : Rageot D, Bohnacker T, Melone A, Langlois JB, Borsari C, Hillmann P, Sele AM, Beaufils F, Zvelebil M, Hebeisen P, Löscher W, Burke J, Fabbro D, Wymann MP.
Abstract : Mechanistic target of rapamycin (mTOR) promotes cell proliferation, growth, and survival and is overactivated in many tumors and central nervous system disorders. PQR620 (3) is a novel, potent, selective, and brain penetrable inhibitor of mTORC1/2 kinase. PQR620 (3) showed excellent selectivity for mTOR over PI3K and protein kinases and efficiently prevented cancer cell growth in a 66 cancer cell line panel. In C57BL/6J and Sprague-Dawley mice, maximum concentration ( Cmax) in plasma and brain was reached after 30 min, with a half-life ( t1/2) > 5 h. In an ovarian carcinoma mouse xenograft model (OVCAR-3), daily dosing of PQR620 (3) inhibited tumor growth significantly. Moreover, PQR620 (3) attenuated epileptic seizures in a tuberous sclerosis complex (TSC) mouse model. In conclusion, PQR620 (3) inhibits mTOR kinase potently and selectively, shows antitumor effects in vitro and in vivo, and promises advantages in CNS indications due to its brain/plasma distribution ratio.
|
Binding affinity to recombinant human GST-tagged mTOR catalytic domain (1360 to 2549 residues) expressed in baculovirus after 1 hr by TR-FRET displacement assay
|
Homo sapiens
|
199.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders.
Year : 2018
Volume : 61
Issue : 22
First Page : 10084
Last Page : 10105
Authors : Rageot D, Bohnacker T, Melone A, Langlois JB, Borsari C, Hillmann P, Sele AM, Beaufils F, Zvelebil M, Hebeisen P, Löscher W, Burke J, Fabbro D, Wymann MP.
Abstract : Mechanistic target of rapamycin (mTOR) promotes cell proliferation, growth, and survival and is overactivated in many tumors and central nervous system disorders. PQR620 (3) is a novel, potent, selective, and brain penetrable inhibitor of mTORC1/2 kinase. PQR620 (3) showed excellent selectivity for mTOR over PI3K and protein kinases and efficiently prevented cancer cell growth in a 66 cancer cell line panel. In C57BL/6J and Sprague-Dawley mice, maximum concentration ( Cmax) in plasma and brain was reached after 30 min, with a half-life ( t1/2) > 5 h. In an ovarian carcinoma mouse xenograft model (OVCAR-3), daily dosing of PQR620 (3) inhibited tumor growth significantly. Moreover, PQR620 (3) attenuated epileptic seizures in a tuberous sclerosis complex (TSC) mouse model. In conclusion, PQR620 (3) inhibits mTOR kinase potently and selectively, shows antitumor effects in vitro and in vivo, and promises advantages in CNS indications due to its brain/plasma distribution ratio.
|
Binding affinity to recombinant N-terminal His6-tagged P110alpha catalytic domain (unknown origin) after 1 hr by TR-FRET displacement assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders.
Year : 2018
Volume : 61
Issue : 22
First Page : 10084
Last Page : 10105
Authors : Rageot D, Bohnacker T, Melone A, Langlois JB, Borsari C, Hillmann P, Sele AM, Beaufils F, Zvelebil M, Hebeisen P, Löscher W, Burke J, Fabbro D, Wymann MP.
Abstract : Mechanistic target of rapamycin (mTOR) promotes cell proliferation, growth, and survival and is overactivated in many tumors and central nervous system disorders. PQR620 (3) is a novel, potent, selective, and brain penetrable inhibitor of mTORC1/2 kinase. PQR620 (3) showed excellent selectivity for mTOR over PI3K and protein kinases and efficiently prevented cancer cell growth in a 66 cancer cell line panel. In C57BL/6J and Sprague-Dawley mice, maximum concentration ( Cmax) in plasma and brain was reached after 30 min, with a half-life ( t1/2) > 5 h. In an ovarian carcinoma mouse xenograft model (OVCAR-3), daily dosing of PQR620 (3) inhibited tumor growth significantly. Moreover, PQR620 (3) attenuated epileptic seizures in a tuberous sclerosis complex (TSC) mouse model. In conclusion, PQR620 (3) inhibits mTOR kinase potently and selectively, shows antitumor effects in vitro and in vivo, and promises advantages in CNS indications due to its brain/plasma distribution ratio.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
97.63
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of recombinant human PI3Kalpha using PIP2 as substrate incubated for 1 hr by kinase-glo assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of 4-Methyl Quinazoline Derivatives as Anticancer Agents Simultaneously Targeting Phosphoinositide 3-Kinases and Histone Deacetylases.
Year : 2019
Volume : 62
Issue : 15
First Page : 6992
Last Page : 7014
Authors : Zhang K, Lai F, Lin S, Ji M, Zhang J, Zhang Y, Jin J, Fu R, Wu D, Tian H, Xue N, Sheng L, Zou X, Li Y, Chen X, Xu H.
Abstract : Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure-activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.
|
Antiproliferative activity against human MDA-MB-453 cells after 96 hrs by MTT assay
|
Homo sapiens
|
370.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of 4-Methyl Quinazoline Derivatives as Anticancer Agents Simultaneously Targeting Phosphoinositide 3-Kinases and Histone Deacetylases.
Year : 2019
Volume : 62
Issue : 15
First Page : 6992
Last Page : 7014
Authors : Zhang K, Lai F, Lin S, Ji M, Zhang J, Zhang Y, Jin J, Fu R, Wu D, Tian H, Xue N, Sheng L, Zou X, Li Y, Chen X, Xu H.
Abstract : Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure-activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.
|
Antiproliferative activity against human HGC27 cells after 96 hrs by MTT assay
|
Homo sapiens
|
990.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of 4-Methyl Quinazoline Derivatives as Anticancer Agents Simultaneously Targeting Phosphoinositide 3-Kinases and Histone Deacetylases.
Year : 2019
Volume : 62
Issue : 15
First Page : 6992
Last Page : 7014
Authors : Zhang K, Lai F, Lin S, Ji M, Zhang J, Zhang Y, Jin J, Fu R, Wu D, Tian H, Xue N, Sheng L, Zou X, Li Y, Chen X, Xu H.
Abstract : Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure-activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.
|
Inhibition of PI3K p110alpha (unknown origin)
|
Homo sapiens
|
52.0
nM
|
|
Journal : Eur J Med Chem
Title : Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer.
Year : 2019
Volume : 183
First Page : 111718
Last Page : 111718
Authors : Elmenier FM, Lasheen DS, Abouzid KAM.
Abstract : Phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signaling cascades in human malignancies. PI3K is genetically mutated or overexpressed in a wide variety of cancers including ovarian, breast, prostate, gastric, colorectal, glioblastoma, endometrial and brain cancers. Studies are still ongoing to find more efficient and selective PI3K inhibitors or dual PI3K inhibitors to overcome the resistance to the current inhibitors. This review will focus on the three main classes of PI3K inhibitors with efficacious antitumor activity which are: isoform-selective PI3K inhibitors, dual pan-Class I PI3K/m-TOR inhibitors, and pan-Class I PI3K inhibitors without significant m-TOR activity. Isoform-selective PI3K inhibitors are classified into four classes IA, IB, II, and III. Moreover, SAR among each class, together with the biological activity will be discussed. In addition, the new scopes for the design of novel candidates to overcome emerging resistance will be highlighted as well.
|
Inhibition of PI3K p110beta (unknown origin)
|
Homo sapiens
|
166.0
nM
|
|
Journal : Eur J Med Chem
Title : Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer.
Year : 2019
Volume : 183
First Page : 111718
Last Page : 111718
Authors : Elmenier FM, Lasheen DS, Abouzid KAM.
Abstract : Phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signaling cascades in human malignancies. PI3K is genetically mutated or overexpressed in a wide variety of cancers including ovarian, breast, prostate, gastric, colorectal, glioblastoma, endometrial and brain cancers. Studies are still ongoing to find more efficient and selective PI3K inhibitors or dual PI3K inhibitors to overcome the resistance to the current inhibitors. This review will focus on the three main classes of PI3K inhibitors with efficacious antitumor activity which are: isoform-selective PI3K inhibitors, dual pan-Class I PI3K/m-TOR inhibitors, and pan-Class I PI3K inhibitors without significant m-TOR activity. Isoform-selective PI3K inhibitors are classified into four classes IA, IB, II, and III. Moreover, SAR among each class, together with the biological activity will be discussed. In addition, the new scopes for the design of novel candidates to overcome emerging resistance will be highlighted as well.
|
Inhibition of PI3K p110delta (unknown origin)
|
Homo sapiens
|
116.0
nM
|
|
Journal : Eur J Med Chem
Title : Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer.
Year : 2019
Volume : 183
First Page : 111718
Last Page : 111718
Authors : Elmenier FM, Lasheen DS, Abouzid KAM.
Abstract : Phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signaling cascades in human malignancies. PI3K is genetically mutated or overexpressed in a wide variety of cancers including ovarian, breast, prostate, gastric, colorectal, glioblastoma, endometrial and brain cancers. Studies are still ongoing to find more efficient and selective PI3K inhibitors or dual PI3K inhibitors to overcome the resistance to the current inhibitors. This review will focus on the three main classes of PI3K inhibitors with efficacious antitumor activity which are: isoform-selective PI3K inhibitors, dual pan-Class I PI3K/m-TOR inhibitors, and pan-Class I PI3K inhibitors without significant m-TOR activity. Isoform-selective PI3K inhibitors are classified into four classes IA, IB, II, and III. Moreover, SAR among each class, together with the biological activity will be discussed. In addition, the new scopes for the design of novel candidates to overcome emerging resistance will be highlighted as well.
|
Inhibition of PI3K p110gamma (unknown origin)
|
Homo sapiens
|
256.0
nM
|
|
Journal : Eur J Med Chem
Title : Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer.
Year : 2019
Volume : 183
First Page : 111718
Last Page : 111718
Authors : Elmenier FM, Lasheen DS, Abouzid KAM.
Abstract : Phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signaling cascades in human malignancies. PI3K is genetically mutated or overexpressed in a wide variety of cancers including ovarian, breast, prostate, gastric, colorectal, glioblastoma, endometrial and brain cancers. Studies are still ongoing to find more efficient and selective PI3K inhibitors or dual PI3K inhibitors to overcome the resistance to the current inhibitors. This review will focus on the three main classes of PI3K inhibitors with efficacious antitumor activity which are: isoform-selective PI3K inhibitors, dual pan-Class I PI3K/m-TOR inhibitors, and pan-Class I PI3K inhibitors without significant m-TOR activity. Isoform-selective PI3K inhibitors are classified into four classes IA, IB, II, and III. Moreover, SAR among each class, together with the biological activity will be discussed. In addition, the new scopes for the design of novel candidates to overcome emerging resistance will be highlighted as well.
|
Inhibition of PI3Kalpha (unknown origin) using PIP2 as substrate measured after 1 hr by ADP-glo plus luminescence assay
|
Homo sapiens
|
52.48
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy.
Year : 2020
Volume : 63
Issue : 1
First Page : 122
Last Page : 139
Authors : Wang J, Li H, He G, Chu Z, Peng K, Ge Y, Zhu Q, Xu Y.
Abstract : Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound <b>15</b> stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kα/δ with pIC<sub>50</sub> values greater than 8. Compound <b>15</b> displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, <b>15</b> showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that <b>15</b>, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.
|
Antiproliferative activity against human A2780 cells measured after 7 days by Celltiter-glo assay
|
Homo sapiens
|
416.87
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy.
Year : 2020
Volume : 63
Issue : 1
First Page : 122
Last Page : 139
Authors : Wang J, Li H, He G, Chu Z, Peng K, Ge Y, Zhu Q, Xu Y.
Abstract : Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound <b>15</b> stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kα/δ with pIC<sub>50</sub> values greater than 8. Compound <b>15</b> displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, <b>15</b> showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that <b>15</b>, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.
|
Inhibition of PI3Kbeta (unknown origin) using PIP2 as substrate measured after 1 hr by ADP-glo plus luminescence assay
|
Homo sapiens
|
165.96
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy.
Year : 2020
Volume : 63
Issue : 1
First Page : 122
Last Page : 139
Authors : Wang J, Li H, He G, Chu Z, Peng K, Ge Y, Zhu Q, Xu Y.
Abstract : Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound <b>15</b> stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kα/δ with pIC<sub>50</sub> values greater than 8. Compound <b>15</b> displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, <b>15</b> showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that <b>15</b>, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.
|
Inhibition of PI3Kdelta (unknown origin) using PIP2 as substrate measured after 2 hrs by ADP-glo plus luminescence assay
|
Homo sapiens
|
114.82
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy.
Year : 2020
Volume : 63
Issue : 1
First Page : 122
Last Page : 139
Authors : Wang J, Li H, He G, Chu Z, Peng K, Ge Y, Zhu Q, Xu Y.
Abstract : Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound <b>15</b> stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kα/δ with pIC<sub>50</sub> values greater than 8. Compound <b>15</b> displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, <b>15</b> showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that <b>15</b>, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.
|
Inhibition of PI3Kgamma (unknown origin) using PIP2 as substrate measured after 1 hr by ADP-glo plus luminescence assay
|
Homo sapiens
|
263.03
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy.
Year : 2020
Volume : 63
Issue : 1
First Page : 122
Last Page : 139
Authors : Wang J, Li H, He G, Chu Z, Peng K, Ge Y, Zhu Q, Xu Y.
Abstract : Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound <b>15</b> stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kα/δ with pIC<sub>50</sub> values greater than 8. Compound <b>15</b> displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, <b>15</b> showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that <b>15</b>, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.
|
Antiproliferative activity against human A2780 cells measured after 7 days in presence of PARP inhibitor olaparib by Celltiter-glo assay
|
Homo sapiens
|
346.74
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy.
Year : 2020
Volume : 63
Issue : 1
First Page : 122
Last Page : 139
Authors : Wang J, Li H, He G, Chu Z, Peng K, Ge Y, Zhu Q, Xu Y.
Abstract : Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound <b>15</b> stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kα/δ with pIC<sub>50</sub> values greater than 8. Compound <b>15</b> displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, <b>15</b> showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that <b>15</b>, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.
|
Antiproliferative activity against human A549 cells measured after 7 days in presence of PARP inhibitor olaparib by Celltiter-glo assay
|
Homo sapiens
|
645.65
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy.
Year : 2020
Volume : 63
Issue : 1
First Page : 122
Last Page : 139
Authors : Wang J, Li H, He G, Chu Z, Peng K, Ge Y, Zhu Q, Xu Y.
Abstract : Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound <b>15</b> stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kα/δ with pIC<sub>50</sub> values greater than 8. Compound <b>15</b> displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, <b>15</b> showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that <b>15</b>, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.
|
Inhibition of PI3K p110alpha/p85 (unknown origin) using PIP2/ATP as substrate after 1 hr by kinase glo luminescent assay
|
Homo sapiens
|
28.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of Substituted Pyrimidines as Potential Phosphatidylinositol 3-Kinase (PI3K) Inhibitors.
Year : 2016
Volume : 59
Issue : 15
First Page : 7268
Last Page : 7274
Authors : Zhang JQ, Luo YJ, Xiong YS, Yu Y, Tu ZC, Long ZJ, Lai XJ, Chen HX, Luo Y, Weng J, Lu G.
Abstract : Three series of substituted pyrimidines were designed and synthesized. All target compounds were screened for kinase inhibitory activities against PI3Kα, and most IC50 values were found within the nanomolar range. Compounds 5d and 5p displayed comparable activities relative to the positive control 5a. 5p also showed a significant isozyme selectivity (PI3Kβ/α). Furthermore, the cytotoxicities of these pyrimidines against human cancer cell lines were evaluated and the in vivo anticancer effect of 5d was also tested.
|
Inhibition of PI3K p110beta/p85 (unknown origin) using PIP2/ATP as substrate after 1 hr by kinase glo luminescent assay
|
Homo sapiens
|
259.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of Substituted Pyrimidines as Potential Phosphatidylinositol 3-Kinase (PI3K) Inhibitors.
Year : 2016
Volume : 59
Issue : 15
First Page : 7268
Last Page : 7274
Authors : Zhang JQ, Luo YJ, Xiong YS, Yu Y, Tu ZC, Long ZJ, Lai XJ, Chen HX, Luo Y, Weng J, Lu G.
Abstract : Three series of substituted pyrimidines were designed and synthesized. All target compounds were screened for kinase inhibitory activities against PI3Kα, and most IC50 values were found within the nanomolar range. Compounds 5d and 5p displayed comparable activities relative to the positive control 5a. 5p also showed a significant isozyme selectivity (PI3Kβ/α). Furthermore, the cytotoxicities of these pyrimidines against human cancer cell lines were evaluated and the in vivo anticancer effect of 5d was also tested.
|
Inhibition of PI3K p110gamma/p101 (unknown origin) using PIP2/ATP as substrate after 1 hr by kinase glo luminescent assay
|
Homo sapiens
|
129.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of Substituted Pyrimidines as Potential Phosphatidylinositol 3-Kinase (PI3K) Inhibitors.
Year : 2016
Volume : 59
Issue : 15
First Page : 7268
Last Page : 7274
Authors : Zhang JQ, Luo YJ, Xiong YS, Yu Y, Tu ZC, Long ZJ, Lai XJ, Chen HX, Luo Y, Weng J, Lu G.
Abstract : Three series of substituted pyrimidines were designed and synthesized. All target compounds were screened for kinase inhibitory activities against PI3Kα, and most IC50 values were found within the nanomolar range. Compounds 5d and 5p displayed comparable activities relative to the positive control 5a. 5p also showed a significant isozyme selectivity (PI3Kβ/α). Furthermore, the cytotoxicities of these pyrimidines against human cancer cell lines were evaluated and the in vivo anticancer effect of 5d was also tested.
|
Inhibition of PI3K p110delta/p85 (unknown origin) using PIP2/ATP as substrate after 1 hr by kinase glo luminescent assay
|
Homo sapiens
|
62.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of Substituted Pyrimidines as Potential Phosphatidylinositol 3-Kinase (PI3K) Inhibitors.
Year : 2016
Volume : 59
Issue : 15
First Page : 7268
Last Page : 7274
Authors : Zhang JQ, Luo YJ, Xiong YS, Yu Y, Tu ZC, Long ZJ, Lai XJ, Chen HX, Luo Y, Weng J, Lu G.
Abstract : Three series of substituted pyrimidines were designed and synthesized. All target compounds were screened for kinase inhibitory activities against PI3Kα, and most IC50 values were found within the nanomolar range. Compounds 5d and 5p displayed comparable activities relative to the positive control 5a. 5p also showed a significant isozyme selectivity (PI3Kβ/α). Furthermore, the cytotoxicities of these pyrimidines against human cancer cell lines were evaluated and the in vivo anticancer effect of 5d was also tested.
|
Antiproliferative activity against human MOLT4 cells after 72 hrs by CCK8 assay
|
Homo sapiens
|
800.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of Substituted Pyrimidines as Potential Phosphatidylinositol 3-Kinase (PI3K) Inhibitors.
Year : 2016
Volume : 59
Issue : 15
First Page : 7268
Last Page : 7274
Authors : Zhang JQ, Luo YJ, Xiong YS, Yu Y, Tu ZC, Long ZJ, Lai XJ, Chen HX, Luo Y, Weng J, Lu G.
Abstract : Three series of substituted pyrimidines were designed and synthesized. All target compounds were screened for kinase inhibitory activities against PI3Kα, and most IC50 values were found within the nanomolar range. Compounds 5d and 5p displayed comparable activities relative to the positive control 5a. 5p also showed a significant isozyme selectivity (PI3Kβ/α). Furthermore, the cytotoxicities of these pyrimidines against human cancer cell lines were evaluated and the in vivo anticancer effect of 5d was also tested.
|
Antiproliferative activity against human U937 cells after 72 hrs by CCK8 assay
|
Homo sapiens
|
580.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of Substituted Pyrimidines as Potential Phosphatidylinositol 3-Kinase (PI3K) Inhibitors.
Year : 2016
Volume : 59
Issue : 15
First Page : 7268
Last Page : 7274
Authors : Zhang JQ, Luo YJ, Xiong YS, Yu Y, Tu ZC, Long ZJ, Lai XJ, Chen HX, Luo Y, Weng J, Lu G.
Abstract : Three series of substituted pyrimidines were designed and synthesized. All target compounds were screened for kinase inhibitory activities against PI3Kα, and most IC50 values were found within the nanomolar range. Compounds 5d and 5p displayed comparable activities relative to the positive control 5a. 5p also showed a significant isozyme selectivity (PI3Kβ/α). Furthermore, the cytotoxicities of these pyrimidines against human cancer cell lines were evaluated and the in vivo anticancer effect of 5d was also tested.
|
Antiproliferative activity against human DU145 cells after 72 hrs by CCK8 assay
|
Homo sapiens
|
910.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of Substituted Pyrimidines as Potential Phosphatidylinositol 3-Kinase (PI3K) Inhibitors.
Year : 2016
Volume : 59
Issue : 15
First Page : 7268
Last Page : 7274
Authors : Zhang JQ, Luo YJ, Xiong YS, Yu Y, Tu ZC, Long ZJ, Lai XJ, Chen HX, Luo Y, Weng J, Lu G.
Abstract : Three series of substituted pyrimidines were designed and synthesized. All target compounds were screened for kinase inhibitory activities against PI3Kα, and most IC50 values were found within the nanomolar range. Compounds 5d and 5p displayed comparable activities relative to the positive control 5a. 5p also showed a significant isozyme selectivity (PI3Kβ/α). Furthermore, the cytotoxicities of these pyrimidines against human cancer cell lines were evaluated and the in vivo anticancer effect of 5d was also tested.
|
Antiproliferative activity against human NCI-N87 cells after 72 hrs by CCK8 assay
|
Homo sapiens
|
660.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of Substituted Pyrimidines as Potential Phosphatidylinositol 3-Kinase (PI3K) Inhibitors.
Year : 2016
Volume : 59
Issue : 15
First Page : 7268
Last Page : 7274
Authors : Zhang JQ, Luo YJ, Xiong YS, Yu Y, Tu ZC, Long ZJ, Lai XJ, Chen HX, Luo Y, Weng J, Lu G.
Abstract : Three series of substituted pyrimidines were designed and synthesized. All target compounds were screened for kinase inhibitory activities against PI3Kα, and most IC50 values were found within the nanomolar range. Compounds 5d and 5p displayed comparable activities relative to the positive control 5a. 5p also showed a significant isozyme selectivity (PI3Kβ/α). Furthermore, the cytotoxicities of these pyrimidines against human cancer cell lines were evaluated and the in vivo anticancer effect of 5d was also tested.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
5.139
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
8.18
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
8.18
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of PI3Kalpha (unknown origin) at 100 nM relative to control
|
Homo sapiens
|
82.0
%
|
|
Journal : Eur J Med Chem
Title : Discovery of novel PARP/PI3K dual inhibitors with high efficiency against BRCA-proficient triple negative breast cancer.
Year : 2021
Volume : 213
First Page : 113054
Last Page : 113054
Authors : Wang J,He G,Li H,Ge Y,Wang S,Xu Y,Zhu Q
Abstract : Co-targeting PARP and PI3K by PARP/PI3K dual inhibitors has been recognized as a promising chemotherapeutic strategy for the treatment of triple negative breast cancer (TNBC) in our previous work. To further explore novel and more potent PARP/PI3K dual inhibitors, a series of compounds were designed, synthesized and evaluated for their pharmacological properties, resulting in the candidate compound 12, a potent and highly selective PARP/PI3K dual inhibitor. Compared to Olaparib, compound 12 exhibits a superior antiproliferative profile against BRCA-proficient MDA-MB-468 cells. In MDA-MB-468 cell-derived xenograft model, compound 12 displayed excellent antitumor efficacy at a dose of 50 mg/kg, which is considerably more efficacious than the single administration of Olaparib or BKM120. Furthermore, compound 12 displayed good metabolic stability and high safety. Taken together, these results suggest that compound 12 as a novel PARP/PI3K dual inhibitor is worthy for further study.
