8K5R

CDK9/cyclin T1 in complex with KB-0742

Summary for 8K5R

• Entry DOI: 10.2210/pdb8k5r/pdb
• Descriptor: Cyclin-dependent kinase 9, Cyclin-T1, (1S,3S)-N3-(5-pentan-3-ylpyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diamine (3 entities in total)
• Functional Keywords: kb-0742, cdk9/cyclin t1, cdk9, cyclin t1, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 68382.80

Authors

Zhou, M.,Li, H.,Gao, H.,Trotter, B.W.,Freeman, D. (deposition date: 2023-07-24, release date: 2023-12-06, Last modification date: 2023-12-27)

Primary citation

Freeman, D.B.,Hopkins, T.D.,Mikochik, P.J.,Vacca, J.P.,Gao, H.,Naylor-Olsen, A.,Rudra, S.,Li, H.,Pop, M.S.,Villagomez, R.A.,Lee, C.,Li, H.,Zhou, M.,Saffran, D.C.,Rioux, N.,Hood, T.R.,Day, M.A.L.,McKeown, M.R.,Lin, C.Y.,Bischofberger, N.,Trotter, B.W.
Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers.
J.Med.Chem., 66:15629-15647, 2023

PubMed Abstract: Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor (). Compound exhibits antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.

PubMed: 37967851
DOI: 10.1021/acs.jmedchem.3c01233

Experimental method

X-RAY DIFFRACTION (3.751 Å)