|
Inhibition of CYP2D6 in human liver microsomes using dextromethorphan as substrate after 30 mins by LC-MS/MS analysis
|
Homo sapiens
|
950.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.
Year : 2012
Volume : 55
Issue : 1
First Page : 169
Last Page : 196
Authors : William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW.
Abstract : Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
|
Inhibition of CDK2 in human MV411 cells assessed as Rb phosphorylation after 24 hrs by Western blot analysis
|
Homo sapiens
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.
Year : 2012
Volume : 55
Issue : 1
First Page : 169
Last Page : 196
Authors : William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW.
Abstract : Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
|
Antiproliferative activity against human DU145 cells after 48 hrs
|
Homo sapiens
|
140.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.
Year : 2012
Volume : 55
Issue : 1
First Page : 169
Last Page : 196
Authors : William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW.
Abstract : Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
|
Antiproliferative activity against human COLO205 cells after 48 hrs
|
Homo sapiens
|
72.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.
Year : 2012
Volume : 55
Issue : 1
First Page : 169
Last Page : 196
Authors : William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW.
Abstract : Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
|
Antiproliferative activity against human Ramos cells after 48 hrs
|
Homo sapiens
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.
Year : 2012
Volume : 55
Issue : 1
First Page : 169
Last Page : 196
Authors : William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW.
Abstract : Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
|
Antiproliferative activity against human HCT116 cells after 48 hrs
|
Homo sapiens
|
79.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.
Year : 2012
Volume : 55
Issue : 1
First Page : 169
Last Page : 196
Authors : William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW.
Abstract : Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
|
Antiproliferative activity against human HL60 cells after 48 hrs
|
Homo sapiens
|
59.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.
Year : 2012
Volume : 55
Issue : 1
First Page : 169
Last Page : 196
Authors : William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW.
Abstract : Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
|
Inhibition of recombinant JAK2 using poly(Glu,Ala,Tyr) as substrate after 2 hrs by luminescence assay
|
None
|
73.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.
Year : 2012
Volume : 55
Issue : 1
First Page : 169
Last Page : 196
Authors : William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW.
Abstract : Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
|
Inhibition of recombinant Flt3 using poly(Glu,Tyr) as substrate after 2 hrs by luminescence assay
|
None
|
56.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.
Year : 2012
Volume : 55
Issue : 1
First Page : 169
Last Page : 196
Authors : William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW.
Abstract : Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
|
Inhibition of recombinant Cdk2/cyclin A using RbING as substrate after 2 hrs by luminescence assay
|
None
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.
Year : 2012
Volume : 55
Issue : 1
First Page : 169
Last Page : 196
Authors : William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW.
Abstract : Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
|
Inhibition of human recombinant FLT3 after 1 hr by LanthaScreen assay platform
|
Homo sapiens
|
42.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Macrocyclic compounds as anti-cancer agents: design and synthesis of multi-acting inhibitors against HDAC, FLT3 and JAK2.
Year : 2015
Volume : 95
First Page : 104
Last Page : 115
Authors : Ning CQ, Lu C, Hu L, Bi YJ, Yao L, He YJ, Liu LF, Liu XY, Yu NF.
Abstract : A novel series of macrocyclic compounds were designed and synthesized as multi-target inhibitors targeting HDAC, FLT3 and JAK2. Some of these compounds exhibited potent HDAC inhibition as well as FLT3 and JAK2 inhibition under both cell-free and cellular conditions. In vitro antiproliferative assay indicated that these compounds were interestingly more cytotoxic to MV4-11 cells bearing FLT3-ITD mutation and HEL cells bearing JAK2(V617F) mutation.
|
Inhibition of human recombinant JAK2 using Z'LYTETry6 peptide substrate after 1 hr by microplate reader
|
Homo sapiens
|
170.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Macrocyclic compounds as anti-cancer agents: design and synthesis of multi-acting inhibitors against HDAC, FLT3 and JAK2.
Year : 2015
Volume : 95
First Page : 104
Last Page : 115
Authors : Ning CQ, Lu C, Hu L, Bi YJ, Yao L, He YJ, Liu LF, Liu XY, Yu NF.
Abstract : A novel series of macrocyclic compounds were designed and synthesized as multi-target inhibitors targeting HDAC, FLT3 and JAK2. Some of these compounds exhibited potent HDAC inhibition as well as FLT3 and JAK2 inhibition under both cell-free and cellular conditions. In vitro antiproliferative assay indicated that these compounds were interestingly more cytotoxic to MV4-11 cells bearing FLT3-ITD mutation and HEL cells bearing JAK2(V617F) mutation.
|
Inhibition of human recombinant GST-tagged JAK2 expressed in baculovirus expression system
|
Homo sapiens
|
73.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of CDK1 (unknown origin)
|
Homo sapiens
|
3.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of human recombinant N-terminal GST-tagged FLT3 D835Y mutant expressed in baculovirus infected Sf21 insect cells using abltide as substrate
|
Homo sapiens
|
21.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of recombinant human full length C-terminal His6-tagged CDK3/N-terminal GST-tagged cyclin E expressed in baculovirus infected Sf21 insect cells using Histone H1 as substrate
|
Homo sapiens
|
3.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of recombinant human full length C-terminal His6-tagged CDK7/cyclin H/N-terminal GST-tagged MAT1 expressed in baculovirus infected Sf21 insect cells using cdk7 substrate peptide
|
Homo sapiens
|
3.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of CDK2 (unknown origin)
|
Homo sapiens
|
3.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of human GST-tagged CDK5
|
Homo sapiens
|
3.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of human GST-tagged CDK9
|
Homo sapiens
|
3.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
23.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
35.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
243.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
930.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
473.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
1.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
319.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
243.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
418.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
579.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
447.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
286.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
850.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
141.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
885.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
996.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
474.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
557.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
311.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
56.54
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of recombinant human C-terminal His6-tagged full length CDK7/untagged recombinant full length human Cyclin H/N-terminal GST-tagged recombinant full length human MAT1 expressed in baculovirus infected Sf21 insect cells using cdk7 peptide as substrate
|
Homo sapiens
|
37.0
nM
|
|
Journal : J Med Chem
Title : Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Year : 2019
Volume : 62
Issue : 9
First Page : 4233
Last Page : 4251
Authors : Tadesse S, Caldon EC, Tilley W, Wang S.
Abstract : Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.
|
Inhibition of recombinant human full-length C-terminal His6-tagged CDK3/full-length human N-terminal GST-tagged Cyclin E expressed in baculovirus infected Sf21 insect cells using histone H1 as substrate
|
Homo sapiens
|
8.0
nM
|
|
Journal : J Med Chem
Title : Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Year : 2019
Volume : 62
Issue : 9
First Page : 4233
Last Page : 4251
Authors : Tadesse S, Caldon EC, Tilley W, Wang S.
Abstract : Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.
|
Inhibition of human recombinant full-length His-tagged CDK1/cyclin B1 expressed in baculovirus expression system
|
Homo sapiens
|
9.0
nM
|
|
Journal : J Med Chem
Title : Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Year : 2019
Volume : 62
Issue : 9
First Page : 4233
Last Page : 4251
Authors : Tadesse S, Caldon EC, Tilley W, Wang S.
Abstract : Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.
|
Inhibition of human recombinant GST-tagged CDK2/cyclin E1
|
Homo sapiens
|
5.0
nM
|
|
Journal : J Med Chem
Title : Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Year : 2019
Volume : 62
Issue : 9
First Page : 4233
Last Page : 4251
Authors : Tadesse S, Caldon EC, Tilley W, Wang S.
Abstract : Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.
|
Inhibition of human recombinant full-length GST/His-tagged CDK5/p25 expressed in baculovirus expression system by Z'-Lyte assay
|
Homo sapiens
|
4.0
nM
|
|
Journal : J Med Chem
Title : Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Year : 2019
Volume : 62
Issue : 9
First Page : 4233
Last Page : 4251
Authors : Tadesse S, Caldon EC, Tilley W, Wang S.
Abstract : Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.
|
Inhibition of human CDK6
|
Homo sapiens
|
100.0
nM
|
|
Journal : J Med Chem
Title : Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Year : 2019
Volume : 62
Issue : 9
First Page : 4233
Last Page : 4251
Authors : Tadesse S, Caldon EC, Tilley W, Wang S.
Abstract : Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.
|
Inhibition of human recombinant full length His-tagged CDK9/cyclin K expressed in baculovirus expression system
|
Homo sapiens
|
3.0
nM
|
|
Journal : J Med Chem
Title : Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Year : 2019
Volume : 62
Issue : 9
First Page : 4233
Last Page : 4251
Authors : Tadesse S, Caldon EC, Tilley W, Wang S.
Abstract : Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
5.53
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
12.59
%
|
|
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
|
-0.37
%
|
|
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
|
-0.28
%
|
|
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
|
-0.28
%
|
|
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
|
-0.37
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of CDK7 (unknown origin)
|
Homo sapiens
|
37.0
nM
|
|
Journal : J Med Chem
Title : Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.
Year : 2020
Volume : 63
Issue : 22
First Page : 13228
Last Page : 13257
Authors : Wu T,Qin Z,Tian Y,Wang J,Xu C,Li Z,Bian J
Abstract : Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).
|
Inhibition of human CDK1
|
Homo sapiens
|
9.0
nM
|
|
Journal : J Med Chem
Title : Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.
Year : 2020
Volume : 63
Issue : 22
First Page : 13228
Last Page : 13257
Authors : Wu T,Qin Z,Tian Y,Wang J,Xu C,Li Z,Bian J
Abstract : Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).
|
Inhibition of human CDK2
|
Homo sapiens
|
5.0
nM
|
|
Journal : J Med Chem
Title : Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.
Year : 2020
Volume : 63
Issue : 22
First Page : 13228
Last Page : 13257
Authors : Wu T,Qin Z,Tian Y,Wang J,Xu C,Li Z,Bian J
Abstract : Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).
|
Inhibition of C-terminal His6-tagged human CDK3/N-terminal GST-tagged human cyclin E
|
Homo sapiens
|
8.0
nM
|
|
Journal : J Med Chem
Title : Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.
Year : 2020
Volume : 63
Issue : 22
First Page : 13228
Last Page : 13257
Authors : Wu T,Qin Z,Tian Y,Wang J,Xu C,Li Z,Bian J
Abstract : Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).
|
Inhibition of human CDK5
|
Homo sapiens
|
4.0
nM
|
|
Journal : J Med Chem
Title : Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.
Year : 2020
Volume : 63
Issue : 22
First Page : 13228
Last Page : 13257
Authors : Wu T,Qin Z,Tian Y,Wang J,Xu C,Li Z,Bian J
Abstract : Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).
|
Inhibition of human CDK9
|
Homo sapiens
|
2.0
nM
|
|
Journal : J Med Chem
Title : Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.
Year : 2020
Volume : 63
Issue : 22
First Page : 13228
Last Page : 13257
Authors : Wu T,Qin Z,Tian Y,Wang J,Xu C,Li Z,Bian J
Abstract : Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).
