2. Academic Validation
  3. Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma

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

Affiliations

  • 1 Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: sbronner@mazetx.com.
  • 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: heffron.timothy@gene.com.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-126244
    CDK4/CDK6 Inhibitor
    CDK