2. Academic Validation
  3. Discovery of novel spiro compound as RAF kinase inhibitor with in vitro potency against KRAS mutant cancer

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

Affiliations

  • 1 Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, NJ 08512, USA. Electronic address: pengebi.zhao@hengrui.com.
  • 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.

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