2. Academic Validation
  3. Discovery of spiro amide SHR902275: A potent, selective, and efficacious RAF inhibitor targeting RAS mutant cancers

Discovery of spiro amide SHR902275: A potent, selective, and efficacious RAF inhibitor targeting RAS mutant cancers

  • Eur J Med Chem. 2022 Jan 15;228:114040. doi: 10.1016/j.ejmech.2021.114040.
Peng Zhao 1,  Linghang Zhuang 2,  Xiangzhu Wang 2,  Song Huang 3,  Heping Wu 2,  Yu Zhou 2,  Yuna Yan 3,  Fan Zhang 2,  Ru Shen 2,  Jing Li 2,  Suxing Liu 2,  Rumin Zhang 2,  Ping Dong 3,  Yuchang Mao 3,  Yuanmin Fan 3,  Chunyong He 3,  Jiakang Sun 3,  Lei Zhang 3,  Qiyue Hu 3,  Hong Wan 3,  Jun Feng 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: 34906761 DOI: 10.1016/j.ejmech.2021.114040
Abstract

The RAS-RAF-MEK-ERK signaling pathway plays a key role to regulate multiple cellular functions. Acquired resistance to the first-generation Raf inhibitors that only targeted the BRafV600E mutation prompted the need for a new generation of Raf inhibitors to target cancers bearing mutant Ras and wild type Raf activity by inhibition of paradoxical activation. Starting from the company's previously reported Raf Inhibitor 1, extensive drug potency and drug-like properties optimizations led to the discovery of molecule 33 (SHR902275) with greatly improved in vitro potency and solubility. Molecule 33 exhibited good DMPK (Drug Metabolism and Pharmacokinetics) properties, excellent permeability, and outstanding mouse/rat oral PK. It was further evaluated in an in vivo Ras mutant Calu6 xenograft mouse model and demonstrated dose dependent efficacy. To achieve high exposure in a toxicity study, pro-drug 48 was also explored.

Keywords

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

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