7M2F

CDK2 with compound 14 inhibitor with carboxylate

7M2F の概要

• エントリーDOI: 10.2210/pdb7m2f/pdb
• 分子名称: Cyclin-dependent kinase 2, [(1r,4r)-4-{4-[4-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydropyridin-1(2H)-yl}cyclohexyl]acetic acid (3 entities in total)
• 機能のキーワード: cdk2, cdk9, kinase inhibitor, signaling protein, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34440.03

構造登録者

Longenecker, K.L.,Qiu, W.,Korepanova, A.,Tong, Y. (登録日: 2021-03-16, 公開日: 2021-07-07, 最終更新日: 2023-10-18)

主引用文献

Tong, Y.,Florjancic, A.S.,Clark, R.F.,Lai, C.,Mastracchio, A.,Zhu, G.D.,Smith, M.L.,Kovar, P.J.,Shaw, B.,Albert, D.H.,Qiu, W.,Longenecker, K.L.,Liu, X.,Olson, A.M.,Osterling, D.J.,Tahir, S.K.,Phillips, D.C.,Leverson, J.D.,Souers, A.J.,Penning, T.D.
Balancing Properties with Carboxylates: A Lead Optimization Campaign for Selective and Orally Active CDK9 Inhibitors.
Acs Med.Chem.Lett., 12:1108-1115, 2021

PubMed Abstract: Cyclin-dependent kinase 9 (CDK9) is a serine/threonine kinase involved in the regulation of transcription elongation. An inhibition of CDK9 downregulates a number of short-lived proteins responsible for tumor maintenance and survival, including the antiapoptotic BCL-2 family member MCL-1. As pan-CDK inhibitors under development have faced dosing and toxicity challenges in the clinical setting, we generated selective CDK9 inhibitors that could be amenable to an oral administration. Here, we report the lead optimization of a series of azaindole-based inhibitors. To overcome early challenges with promiscuity and cardiovascular toxicity, carboxylates were introduced into the pharmacophore en route to compounds such as and . These CDK9 inhibitors demonstrated a reduced toxicity, adequate pharmacokinetic properties, and a robust in vivo efficacy in mice upon oral dosing.

PubMed: 34267880
DOI: 10.1021/acsmedchemlett.1c00161

実験手法

X-RAY DIFFRACTION (1.632 Å)