Discovery of novel 2-aminopyridine derivatives as ROS1 and ALK dual inhibitors to combat drug-resistant mutants including ROS1^G2032R and ALK^G1202R

Abstract

Clinical treatment by FDA-approved ROS1/ALK inhibitor Crizotinib significantly improved the therapeutic outcomes. However, the emergence of drug resistance, especially driven by acquired mutations, have become an inevitable problem and worsened the clinical effects of Crizotinib. To combat drug resistance, some novel 2-aminopyridine derivatives were designed rationally based on molecular simulation, then synthesised and subjected to biological test. The preferred spiro derivative C01 exhibited remarkable activity against CD74-ROS1^G2032R cell with an IC₅₀ value of 42.3 nM, which was about 30-fold more potent than Crizotinib. Moreover, C01 also potently inhibited enzymatic activity against clinically Crizotinib-resistant ALK^G1202R, harbouring a 10-fold potency superior to Crizotinib. Furthermore, molecular dynamic disclosed that introducing the spiro group could reduce the steric hindrance with bulky side chain (Arginine) in solvent region of ROS1^G2032R, which explained the sensitivity of C01 to drug-resistant mutant. These results indicated a path forward for the generation of anti Crizotinib-resistant ROS1/ALK dual inhibitors.

GRAPHICAL ABSTRACT

Highlight

• SAR of a series of 2-aminopyridine ROS1/ALK inhibitors was studied.

• The spiro derivatives exhibited remarkable dual ROS1/ALK activity.

• C01 potently inhibited Crizotinib-refractory ALK^G1202R and ROS1^G2032R mutants.

• Molecular simulations gave a probable explanation for the activity of C01.

Keywords:

• 2-Aminopyridine derivatives ROS1/ALK dual inhibitors ROS1^G2032R
• ALK^G1202R
• anti-drug-resistant

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by grants from National Science Foundation of China (No. 81573263), China postdoctoral Science Foundation (No. 2022M711531), Natural Science Foundation of Guangdong Province (No. 2021A1515011246), Key Research and Development Plan of Guangzhou, China (No. 202103000077).