7NXK

Crystal structure of human Cdk12/Cyclin K in complex with the inhibitor BSJ-01-175

Summary for 7NXK

• Entry DOI: 10.2210/pdb7nxk/pdb
• Descriptor: Cyclin-dependent kinase 12, Cyclin-K, (E)-N-[4-[(1R,3R)-3-[[5-chloranyl-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]cyclohexyl]oxyphenyl]-4-(dimethylamino)but-2-enamide, ... (4 entities in total)
• Functional Keywords: cdk12, cyclin k, ccnk, bsj-01-175, kinase, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 145478.48

Authors

Anand, K.,Dust, S.,Kaltheuner, I.H.,Geyer, M. (deposition date: 2021-03-18, release date: 2021-05-12, Last modification date: 2024-01-31)

Primary citation

Jiang, B.,Jiang, J.,Kaltheuner, I.H.,Iniguez, A.B.,Anand, K.,Ferguson, F.M.,Ficarro, S.B.,Seong, B.K.A.,Greifenberg, A.K.,Dust, S.,Kwiatkowski, N.P.,Marto, J.A.,Stegmaier, K.,Zhang, T.,Geyer, M.,Gray, N.S.
Structure-activity relationship study of THZ531 derivatives enables the discovery of BSJ-01-175 as a dual CDK12/13 covalent inhibitor with efficacy in Ewing sarcoma.
Eur.J.Med.Chem., 221:113481-113481, 2021

PubMed Abstract: Development of inhibitors targeting CDK12/13 is of increasing interest as a potential therapy for cancers as these compounds inhibit transcription of DNA damage response (DDR) genes. We previously described THZ531, a covalent inhibitor with selectivity for CDK12/13. In order to elucidate structure-activity relationship (SAR), we have undertaken a medicinal chemistry campaign and established a focused library of THZ531 analogs. Among these analogs, BSJ-01-175 demonstrates exquisite selectivity, potent inhibition of RNA polymerase II phosphorylation, and downregulation of CDK12-targeted genes in cancer cells. A 3.0 Å co-crystal structure with CDK12/CycK provides a structural rational for selective targeting of Cys1039 located in a C-terminal extension from the kinase domain. With moderate pharmacokinetic properties, BSJ-01-175 exhibits efficacy against an Ewing sarcoma tumor growth in a patient-derived xenograft (PDX) mouse model following 10 mg/kg once a day, intraperitoneal administration. Taken together, BSJ-01-175 represents the first selective CDK12/13 covalent inhibitor with in vivo efficacy reported to date.

PubMed: 33945934
DOI: 10.1016/j.ejmech.2021.113481

Experimental method

X-RAY DIFFRACTION (3 Å)