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
  • 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: [email protected].
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.