7M2F
CDK2 with compound 14 inhibitor with carboxylate
Summary for 7M2F
| Entry DOI | 10.2210/pdb7m2f/pdb |
| Descriptor | 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) |
| Functional Keywords | cdk2, cdk9, kinase inhibitor, signaling protein, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 34440.03 |
| Authors | Longenecker, K.L.,Qiu, W.,Korepanova, A.,Tong, Y. (deposition date: 2021-03-16, release date: 2021-07-07, Last modification date: 2023-10-18) |
| Primary citation | 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 Cited by 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: 34267880DOI: 10.1021/acsmedchemlett.1c00161 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.632 Å) |
Structure validation
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