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  3. Discovery of Isoform-Selective Akt3 Degraders Overcoming Osimertinib-Induced Resistance in Non-Small Cell Lung Cancer Cells

Discovery of Isoform-Selective Akt3 Degraders Overcoming Osimertinib-Induced Resistance in Non-Small Cell Lung Cancer Cells

  • J Med Chem. 2022 Oct 27;65(20):14032-14048. doi: 10.1021/acs.jmedchem.2c01246.
Fang Xu 1 2,  Xin Zhang 1 2,  Zhipeng Chen 3,  Sheng He 1,  Jing Guo 1,  Lei Yu 1,  Yongjin Wang 1,  Caiyun Hou 1,  Hawaa Ai-Furas 1,  Zongyao Zheng 3,  Jeff B Smaill 4,  Adam V Patterson 4,  Zhi-Min Zhang 1,  Liang Chen 3,  Xiaomei Ren 5,  Ke Ding 1 2 5
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of PR China, College of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 2 The First Affiliated Hospital (Huaqiao Hospital), Jinan University, Guangzhou 510632, China.
  • 3 MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
  • 4 Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland 1142, New Zealand.
  • 5 State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 210530, China.
PMID: 36173763 DOI: 10.1021/acs.jmedchem.2c01246
Abstract

EGFR inhibitor therapies have brought significant benefit to NSCLC patients. However, all patients gradually progress to acquired resistance via diverse mechanisms. Akt3 overexpression but not Akt1/2 is one of the found molecular events that mediate osimertinib (1) resistance in NSCLC patients. Here, we report 12l as the first bona fide isoform-selective Akt3 degrader which potently induced proteasomal degradation of the target both in vitro and in vivo, whereas its effects on Akt1/2 were minimal. Using 12l as a tool, non-canonical function of Akt3 was validated to contribute greatly to survival of 1-resistant H1975OR NSCLC cells. Degrader 12l potently suppressed the growth of H1975OR as well as several NSCLC cell lines with low nanomolar IC50 values and demonstrated promising in vivo antitumor efficacy in nude mice bearing H1975OR or PC9 NSCLC xenograft models. Selective degradation of Akt3 may be considered as a novel strategy for human Cancer therapy.

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