|
Inhibition of human recombinant full length His-tagged ABL1 T315I mutant expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
52.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Ex vivo inhibition of anti IgD-induced CD86 expression in C57BL/6 mouse whole blood B cells administered as single dose via oral gavage 30 mins prior to IgD stimulation measured after 3 hrs by flow cytometric analysis
|
Mus musculus
|
24.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length His-tagged STK22D expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
71.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length GST-tagged SNF1LK2 expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
72.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human C-terminal 6His-tagged SYK (356 to 635 residues) expressed in Sf9 insect cells using 5-carboxyfluorescein(FAM)-EEPLYWSFPAKKK-NH2 as substrate after 1 hr in presence of ATP by electrophoretic mobility shift assay
|
Homo sapiens
|
3.2
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of SYK in TgM-stimulated human Ramos cells expressing RA1/GFP-tagged BLNK assessed as reduction in RA1/GFP-tagged BLNK phosphorylation preincubated for 1 hr followed by IgM stimulation for 20 mins by TR-FRET assay
|
Homo sapiens
|
9.8
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human ERG at 10 uM
|
Homo sapiens
|
10.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human N-terminal 6His-tagged FLT3 (564 to 993 residues) expressed in Sf9 insect cells using 5-carboxyfluorescein(FAM)-KKKKEEIYFFFG-NH2 as substrate after 1 hr in presence of ATP by electrophoretic mobility shift assay
|
Homo sapiens
|
4.6
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged JAK3 expressed in baculovirus expression system using 5-carboxyfluorescein(FAM)-EEPLYWSFPAKKK-NH2 as substrate after 1 hr in presence of ATP by electrophoretic mobility shift assay
|
Homo sapiens
|
114.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human N-terminal 6His-tagged VEGFR2 (807 to 1171 residues) expressed in Sf9 insect cells using 5-carboxyfluorescein(FAM)-EEPLYWSFPAKKK-NH2 as substrate after 1 hr in presence of ATP by electrophoretic mobility shift assay
|
Homo sapiens
|
135.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human full length N-terminal GST-tagged ZAP-70 (1 to 619 residues) expressed in baculovirus expression system using ULight peptide as substrate after 1 hr in presence of ATP by TR-FRET assay
|
Homo sapiens
|
75.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length N-terminal GST-tagged SYK cytoplasmic domain expressed in baculovirus expression system by Z'-LYTE assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length His-tagged CHK1 expressed in baculovirus expression system by Z'-LYTE assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged EPHA1 cytoplasmic domain (568 to 976 residues) expressed in baculovirus expression system by Z'-LYTE assay
|
Homo sapiens
|
31.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant FER cytoplasmic domain (541 to 822 residues) expressed in baculovirus expression system by Z'-LYTE assay
|
Homo sapiens
|
51.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant His-tagged FLT3 D835Y mutant cytoplasmic domain (564 to 958 residues) expressed in baculovirus expression system by Z'-LYTE assay
|
Homo sapiens
|
22.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged RET cytoplasmic domain (658 to 1114 residues) expressed in baculovirus expression system by Z'-LYTE assay
|
Homo sapiens
|
19.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged PAK4 catalytic domain (295 to 591 residues) expressed in baculovirus expression system by Z'-LYTE assay
|
Homo sapiens
|
76.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged PDGFRalpha V561D mutant cytoplasmic domain (550 to 1089 residues) expressed in baculovirus expression system by Z'-LYTE assay
|
Homo sapiens
|
45.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length N-terminal GST-tagged PHKG2 expressed in baculovirus expression system by Z'-LYTE assay
|
Homo sapiens
|
226.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of recombinant human N-terminal GST-tagged RET V791F mutant cytoplasmic domain (658 to 1114 residues) expressed in baculovirus expression system by Z'-LYTE assay
|
Homo sapiens
|
5.2
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant N-terminal GST-tagged RET V804L mutant cytoplasmic domain (658 to 1114 residues) expressed in baculovirus expression system by Z'-LYTE assay
|
Homo sapiens
|
8.4
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant His-tagged VEGFR2 cytoplasmic domain (789 to1356 residues) expressed in baculovirus expression system by Z'-LYTE assay
|
Homo sapiens
|
88.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length His-tagged ABL1 Y253F mutant cytoplasmic domain expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
59.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length His-tagged CHK1 expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
84.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length His-tagged ABL1 G250E mutant cytoplasmic domain expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
63.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length His-tagged CHK2 expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
63.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant His-tagged FMS cytoplasmic domain (538 to 910 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
63.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged EPHA1 cytoplasmic domain (568 to 976 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
85.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged EPHB1 cytoplasmic domain (613 to 881 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
59.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant FER cytoplasmic domain (541 to 822 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
80.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant His-tagged FLT3 cytoplasmic domain (564 to 958 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
68.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant His-tagged FLT3 D835Y mutant cytoplasmic domain (564 to 958 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
98.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged VEGFR3 cytoplasmic domain (800 to 1297 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
75.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length His-tagged IRAK4 expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
51.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged JAK2 cytoplasmic domain (809 to 1153 +9 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
53.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged JAK3 cytoplasmic domain (781 to 1124 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
56.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant His-tagged VEGFR2 cytoplasmic domain (789 to1356 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
68.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human full length DYKDDDDK-tagged LRRK2 expressed in baculovirus expression system at 200 nM by adapta assay
|
Homo sapiens
|
70.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human full length DYKDDDDK-tagged LRRK2 G2019S mutant expressed in mammalian expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
74.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length C-terminal His-tagged LYN B cytoplasmic domain expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
59.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length His-tagged MAP4K2 expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
57.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length GST-tagged MAP4K5 expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
57.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length GST-tagged MARK3 expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
58.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length GST-tagged MARK4 expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
52.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged MERTK cytoplasmic domain (578 to 872 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
68.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant His-tagged NTRK1 cytoplasmic domain (441 to 796 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
59.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant His-tagged NTRK2 cytoplasmic domain (526 to 838 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
63.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant His-tagged NTRK3 cytoplasmic domain (510 to 825 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
68.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length His-tagged NUAK1 (510 to 825 residues) expressed in baculovirus expression system at 200 nM by adapta assay
|
Homo sapiens
|
63.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged PAK4 catalytic domain (295 to 591 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
80.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant His-tagged PAK7 catalytic domain (425 to 719 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
67.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged PDGFRalpha cytoplasmic domain (550 to 1089 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
52.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged PDGFRalpha V561D mutant cytoplasmic domain (550 to 1089 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
81.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length N-terminal GST-tagged PHKG2 expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
66.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length GST-tagged PTK2 cytoplasmic domain expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
50.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged RET cytoplasmic domain (658 to 1114 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
103.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant N-terminal GST-tagged RET V804L mutant cytoplasmic domain (658 to 1114 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
99.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of recombinant human N-terminal GST-tagged RET V791F mutant cytoplasmic domain (658 to 1114 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
103.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant GST-tagged ROS1 cytoplasmic domain (1883 to 2347 residues) expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
57.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Cytotoxicity against FLT3-ITD dependent human MV411 cells assessed as decrease in cell viability after 72 to 96 hrs by MTS assay
|
Homo sapiens
|
18.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Cytotoxicity against FLT3-ITD dependent human MOLM13 cells assessed as decrease in cell viability after 72 to 96 hrs by MTS assay
|
Homo sapiens
|
110.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length His-tagged FES cytoplasmic domain expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
62.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
Inhibition of human recombinant full length C-terminal His-tagged FGR cytoplasmic domain expressed in baculovirus expression system at 200 nM by Z'-LYTE assay
|
Homo sapiens
|
62.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Year : 2016
Volume : 26
Issue : 24
First Page : 5947
Last Page : 5950
Authors : Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z.
Abstract : Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.76
%
|
|
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
|
0.39
%
|
|
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
|
0.39
%
|
|
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.
