Development of Alectinib-Based PROTACs as Novel Potent Degraders of Anaplastic Lymphoma Kinase (ALK)

  • J Med Chem. 2021 Jul 8;64(13):9120-9140. doi: 10.1021/acs.jmedchem.1c00270.
Shaowen Xie  1 ,  Yuan Sun  1 ,  Yulin Liu  1  2 ,  Xinnan Li  1 ,  Xinuo Li  3 ,  Wenyi Zhong  2 ,  Feiyan Zhan  1 ,  Jingjie Zhu  1 ,  Hong Yao  1 ,  Dong-Hua Yang  4 ,  Zhe-Sheng Chen  4 ,  Jinyi Xu  1 ,  Shengtao Xu  1
Affiliations
  • 1. State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
  • 2. Department of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
  • 3. Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
  • 4. College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York 11439, United States.
PMID: 34176264 DOI: 10.1021/acs.jmedchem.1c00270
Abstract

A series of novel anaplastic lymphoma kinase (ALK) degraders were designed and synthesized based on proteolysis-targeting chimera (PROTAC) technology by linking two alectinib analogs (36 and 37) with pomalidomide through linkers of different lengths and types. The most promising degrader 17 possessed a high ALK-binding affinity and potent antiproliferative activity in the ALK-dependent cell lines and did not exhibit obvious cytotoxicity in ALK fusion-negative cells. More importantly, the efficacy of compound 17 in a Karpas 299 xenograft mouse model was further evaluated based on its ALK-sustained degradation ability in vivo. The reduction in tumor weight in the compound 17-treated group (10 mg/kg/day, I.V.) reached 75.82%, while alectinib reduced tumor weight by 63.82% at a dose of 20 mg/kg/day (P.O.). Taken together, our findings suggest that alectinib-based PROTACs associated with the degradation of ALK may have promising beneficial effects for treating ALK-driven malignancies.

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