2. Academic Validation
  3. Discovery and preclinical evaluations of WX-0593, a novel ALK inhibitor targeting crizotinib-resistant mutations

Discovery and preclinical evaluations of WX-0593, a novel ALK inhibitor targeting crizotinib-resistant mutations

  • Bioorg Med Chem Lett. 2022 Jun 15:66:128730. doi: 10.1016/j.bmcl.2022.128730.
Xile Liu 1,  Lu Zhang 1,  Haiwen Wan 1,  Zhenzhen Zhu 1,  Jing Jin 1,  Yuxin Qin 1,  Weifeng Mao 1,  Kang Yan 1,  Douglas Fang 1,  Wen Jiang 1,  Lihong Hu 1,  Jinhua Chen 1,  Kevin Chen 1,  Shuhui Chen 1,  Jian Li 1,  Shuyong Zhao 2,  Shansong Zheng 2,  Long Zhang 2,  Charles Z Ding 3
Affiliations

Affiliations

  • 1 WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
  • 2 Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co., Ltd., No. 243 Gong Ye Bei Road, Jinan, Shandong Province 250100, People's Republic of China.
  • 3 WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China. Electronic address: charles_ding@wuxiapptec.com.
PMID: 35421578 DOI: 10.1016/j.bmcl.2022.128730
Abstract

ALK gene rearrangements are oncogenic drivers in approximately 5% of NSCLC. Crizotinib, a first generation ALK inhibitor, is widely prescribed for ALK-positive NSCLC in clinic. Resistance to crizotinib and Other ALK inhibitors has been problematic. Addressing resistance, here we describe discovery and development of a novel, proprietary spirocyclic diamine-substituted aryl phosphine oxide series of inhibitors, which led to the identification of WX-0593 (16a) as a potent ALK inhibitor. WX-0593 inhibited the activity of both wild type and resistant mutants of ALK in vitro, showed strong antitumor activity in a crizotinib-resistant mouse PDX model. WX-0593 is currently under development in phase II/III clinical trials.

Keywords

ALK; ALK inhibitor; Crizotinib resistance; Phosphine oxide.

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