Discovery of novel spiro compound as RAF kinase inhibitor with in vitro potency against KRAS mutant cancer

  • Bioorg Med Chem Lett. 2022 May 1:63:128666. doi: 10.1016/j.bmcl.2022.128666.
Peng Zhao  1 ,  Xiangzhu Wang  2 ,  Linghang Zhuang  2 ,  Song Huang  3 ,  Yu Zhou  2 ,  Yuna Yan  3 ,  Ru Shen  2 ,  Fan Zhang  2 ,  Jie Li  3 ,  Qiyue Hu  3 ,  Suxing Liu  2 ,  Rumin Zhang  2 ,  Ping Dong  3 ,  Hong Wan  3 ,  Chang Bai  3 ,  Feng He  3 ,  Weikang Tao  3
Affiliations
  • 1. Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, NJ 08512, USA. Electronic address: [email protected].
  • 2. Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, NJ 08512, USA.
  • 3. Shanghai Hengrui Pharmaceutical Co. Ltd., 279 Wenjing Road, Shanghai 200245, China.
PMID: 35276360 DOI: 10.1016/j.bmcl.2022.128666
Abstract

The development of Raf inhibitors targeting cancers with wild type Raf kinase and/or Ras mutation has been challenging due to the paradoxical activation of the RAS-RAF-MEK-ERK cascade following Raf Inhibitor treatment. Herein is the discovery and optimization of a series of Raf inhibitors with a novel spiro structure. The most potent spiro molecule 9 showed excellent in vitro potency against b/c RAF Enzymes and Ras mutant H358 Cancer cells with minimal paradoxical Raf signaling activation. Compound 9 also exhibited good drug-like properties as demonstrated by in vitro Cytochrome P450 (CYP), liver microsome stability (LMS) data and moderate oral pharmacokinetics (PK) profiles in rat and mouse.

Keywords
Kinase inhibitor; Mutation; Paradoxical activation; RAF; RAS; Spiro compound.