Design, Synthesis, and Biological Evaluation of Novel Diaminopyrimidine Macrocycles as Fourth Generation Reversible EGFR Inhibitors That Overcome Clinical Resistance to Osimertinib Mediated by C797S Mutation

Shiliang Hu; Linjiang Tong; Qiao Qin; Jiaxin Wen; Yan Li; Fang Feng; Kunzhong Wu; Yang Zhou; Jinsai Shang; Junjian Wang; Jinbao Liu; Hua Xie; Xiaoyun Lu

doi:10.1021/acs.jmedchem.4c01975

Design, Synthesis, and Biological Evaluation of Novel Diaminopyrimidine Macrocycles as Fourth Generation Reversible EGFR Inhibitors That Overcome Clinical Resistance to Osimertinib Mediated by C797S Mutation

J Med Chem. 2024 Nov 13. doi: 10.1021/acs.jmedchem.4c01975. Online ahead of print.

Authors

Shiliang Hu¹, Linjiang Tong², Qiao Qin¹, Jiaxin Wen^{2

3

4}, Yan Li², Fang Feng², Kunzhong Wu⁵, Yang Zhou¹, Jinsai Shang⁵, Junjian Wang⁶, Jinbao Liu⁷, Hua Xie^{2

3

4}, Xiaoyun Lu^{1

8}

Affiliations

¹ State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China.
² Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
⁴ University of Chinese Academy of Sciences, Beijing 100049, China.
⁵ School of Basic Medical Sciences, Guangzhou National Laboratory, Guangzhou Medical University, Guangzhou 511436, China.
⁶ Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
⁷ State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
⁸ Department of Hematology, Guangdong Second Provincial General Hospital, Jinan University, Guangzhou 510632, China.

PMID: 39536262
DOI: 10.1021/acs.jmedchem.4c01975

Abstract

Overcoming clinical resistance to osimertinib mediated by the tertiary C797S mutation remains an unmet medical need. To date, there are no effective drugs that have been approved for patients who harbor EGFR^T790M/C797S mutations. Herein, we applied a structure-based drug design strategy to discover a series of potent and selective diaminopyrimidine macrocycles as novel EGFR^T790M/C797S inhibitors. The representative compound 21v potently inhibited EGFR^{19del/T790M/C797S} and EGFR^{L858R/T790M/C797S} mutants with IC₅₀ values of 2.3 nM and 12.5 nM, respectively, and exhibited antiproliferative activity against Ba/F3-EGFR^{19del/T790M/C797S} and Ba/F3-EGFR^{L858R/T790M/C797S} cells with IC₅₀ values of 41 and 52 nM, respectively. Further, 21v inhibited proliferation of the EGFR^{19del/T790M/C797S} mutant PC-9-OR NSCLC cell line with an IC₅₀ value of 56 nM and displayed selectivity over parental Ba/F3 and A431 cells. Moreover, 21v exhibited antitumor efficacy in a Ba/F3-EGFR^{19del/T790M/C797S} xenograft model. This study provides a promising macrocyclic lead for anticancer drug discovery overcoming EGFR^C797S mutation mediated resistance in NSCLC patients.