Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Bronner, Sarah M.¹  Merrick, Karl A.¹  Murray, Jeremy¹  Salphati, Laurent¹  Moffat, John G.¹  Pang, Jodie¹  Sneeringer, Christopher J.¹  Dompe, Nicholas¹  Cyr, Patrick¹  Purkey, Hans¹  Boenig, Gladys de Leon¹  Li, Jun¹  Kolesnikov, Aleksandr¹  Larouche-Gauthier, Robin²  Lai, Kwong Wah³  Shen, Xiaoli³  Aubert-Nicol, Samuel²  Chen, Yi-Chen¹  Cheong, Jonathan¹  Crawford, James J.¹  Hafner, Marc¹  Haghshenas, Pouyan²  Jakalian, Araz²  Leclerc, Jean-Philippe²  Lim, Ngiap-Kie¹  O'Brien, Tom¹  Plise, Emile G.¹  Shalan, Hadil¹  Sturino, Claudio²  Wai, John³  Xiao, Yang¹  Yin, Jianping¹  Zhao, Liang²  Gould, Stephen¹  Olivero, Alan¹  Heffron, Timothy P.¹ 

[1] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA

[2] Paraza Pharma Inc, 2525 Ave Marie Curie, Montreal, PQ H45 2E1, Canada

[3] WuXi AppTec Co Ltd, 288 Fute Zhong Rd, Shanghai 200131, Peoples R China

关键词: Kinase;    CDK4;    CDK6;    Glioblastoma;    Brain penetration;   

DOI  :  10.1016/j.bmcl.2019.06.021

来源: Elsevier

【 摘 要 】

CDK4 and CDK6 are kinases with similar sequences that regulate cell cycle progression and are validated targets in the treatment of cancer. Glioblastoma is characterized by a high frequency of CDKN2A/CCND2/CDK4/CDK6 pathway dysregulation, making dual inhibition of CDK4 and CDK6 an attractive therapeutic approach for this disease. Abemaciclib, ribociclib, and palbociclib are approved CDK4/6 inhibitors for the treatment of HR+/HER2- breast cancer, but these drugs are not expected to show strong activity in brain tumors due to poor blood brain barrier penetration. Herein, we report the identification of a brain-penetrant CDK4/6 inhibitor derived from a literature molecule with low molecular weight and topological polar surface area (MW = 285 and TPSA = 66 angstrom(2)), but lacking the CDK2/1 selectivity profile due to the absence of a basic amine. Removal of a hydrogen bond donor via cyclization of the pyrazole allowed for the introduction of basic and semi-basic amines, while maintaining in many cases efflux ratios reasonable for a CNS program. Ultimately, a basic spiroazetidine (cpK(a) = 8.8) was identified that afforded acceptable selectivity over anti-target CDK1 while maintaining brain-penetration in vivo (mouse K-p,K-uu = 0.20-0.59). To probe the potency and selectivity, our lead compound was evaluated in a panel of glioblastoma cell lines. Potency comparable to abemaciclib was observed in Rb-wild type lines U87MG, DBTRG-05MG, A172, and T98G, while Rb-deficient cell lines SF539 and M059J exhibited a lack of sensitivity.

【 授权许可】

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