7RA5

CDK2 IN COMPLEX WITH COMPOUND 4

Summary for 7RA5

• Entry DOI: 10.2210/pdb7ra5/pdb
• Descriptor: Cyclin-dependent kinase 2, 4-[7-(methanesulfonyl)-1H-indol-3-yl]-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (3 entities in total)
• Functional Keywords: cdk2, cyclin-dependent kinase 2, proteros biostructures gmbh, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 34544.08

Authors

Marineau, J.J.,Malojcic, G. (deposition date: 2021-06-30, release date: 2021-11-03, Last modification date: 2024-04-03)

Primary citation

Marineau, J.J.,Hamman, K.B.,Hu, S.,Alnemy, S.,Mihalich, J.,Kabro, A.,Whitmore, K.M.,Winter, D.K.,Roy, S.,Ciblat, S.,Ke, N.,Savinainen, A.,Wilsily, A.,Malojcic, G.,Zahler, R.,Schmidt, D.,Bradley, M.J.,Waters, N.J.,Chuaqui, C.
Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7.
J.Med.Chem., 65:1458-1480, 2022

PubMed Abstract: CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of , a highly potent (sub-nM CDK7 K) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.

PubMed: 34726887
DOI: 10.1021/acs.jmedchem.1c01171

Experimental method

X-RAY DIFFRACTION (1.67 Å)