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

  • Bioorg Med Chem Lett. 2019 Aug 15;29(16):2294-2301. doi: 10.1016/j.bmcl.2019.06.021.
Sarah M Bronner  1 ,  Karl A Merrick  2 ,  Jeremy Murray  2 ,  Laurent Salphati  2 ,  John G Moffat  2 ,  Jodie Pang  2 ,  Christopher J Sneeringer  2 ,  Nicholas Dompe  2 ,  Patrick Cyr  2 ,  Hans Purkey  2 ,  Gladys de Leon Boenig  2 ,  Jun Li  2 ,  Aleksandr Kolesnikov  2 ,  Robin Larouche-Gauthier  3 ,  Kwong Wah Lai  4 ,  Xiaoli Shen  4 ,  Samuel Aubert-Nicol  3 ,  Yi-Chen Chen  2 ,  Jonathan Cheong  2 ,  James J Crawford  2 ,  Marc Hafner  2 ,  Pouyan Haghshenas  3 ,  Araz Jakalian  3 ,  Jean-Philippe Leclerc  3 ,  Ngiap-Kie Lim  2 ,  Tom O'Brien  2 ,  Emile G Plise  2 ,  Hadil Shalan  2 ,  Claudio Sturino  3 ,  John Wai  4 ,  Yang Xiao  2 ,  Jianping Yin  2 ,  Liang Zhao  3 ,  Stephen Gould  2 ,  Alan Olivero  2 ,  Timothy P Heffron  5
Affiliations
  • 1. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: [email protected].
  • 2. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 3. Paraza Pharma, Inc., 2525 Ave. Marie-Curie, Montreal, QC H4S 2E1, Canada.
  • 4. WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
  • 5. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: [email protected].
PMID: 31307887 DOI: 10.1016/j.bmcl.2019.06.021
Abstract

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 Å2), 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 (cpKa = 8.8) was identified that afforded acceptable selectivity over anti-target CDK1 while maintaining brain-penetration in vivo (mouse Kp,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.

Keywords
Brain penetration; CDK4; CDK6; Glioblastoma; Kinase.
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