8K5R

CDK9/cyclin T1 in complex with KB-0742

8K5R の概要

• エントリーDOI: 10.2210/pdb8k5r/pdb
• 分子名称: 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)
• 機能のキーワード: kb-0742, cdk9/cyclin t1, cdk9, cyclin t1, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 68382.80

構造登録者

Zhou, M.,Li, H.,Gao, H.,Trotter, B.W.,Freeman, D. (登録日: 2023-07-24, 公開日: 2023-12-06, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.751 Å)