Design and development of novel EGFR inhibitors spanning all subgroups of EGFR mutations in non-small cell lung cancer

Public summary

* A conserved subpocket behind ATP-binding domain was discovered across all subgroups of EGFR mutations.

* This finding suggests the possibility of rational designed pan-EGFR inhibitors.

* ZW-49 is the only rationally designed pan-EGFR inhibitor with IC50 values at 0.03–1.5 nM.

* ZW-49 is currently in phase 1 clinical trials (CTR20212743).

* Based on a metabolic-driven drug optimization strategy, ZW-49b with improved PK properties was developed.

Abstract

EGFR mutations are common in non-small cell lung cancer (NSCLC), with classical mutations (L858R and exon 19 deletions [Ex19del]) and T790M mutation responsive to three generations of EGFR inhibitors (TKIs). However, the other 30% EGFR mutations, which are classified into exon 20 insertions (Ex20ins) and PACC (P loop/αC-helix compressing) often confer resistance to current TKIs, thereby inducing limited clinical efficacy. In this article, a conserved subpocket behind the ATP-binding domain was detected with our precursor from in-house virtual screening and structural superposition against all subgroups of mutations. This subpocket was utilized combining with traditional ATP pocket in the design and optimization of pan-EGFR inhibitors. The representative compound ZW-49 could potently inhibit all subgroups of EGFR mutations with selectivity over wild-type EGFR and other target families. By means of in silico simulations, we further elucidate the key sites within the subpocket that significantly contribute to the binding of the Ex20ins and PACC mutations with ZW-49. Furthermore, ZW-49 could efficiently induce tumor regression in multiple xenograft models. Deuterated derivatives of ZW-49 were designed by predicting and modifying the sites of metabolism that exhibited improved PK properties while retaining inhibition activities against all subgroups of EGFR mutations. Our work suggests a pan-EGFR inhibitor development strategy to address EGFR mutational heterogeneity for NSCLC including structure-based drug design and metabolic optimization. We also provided ZW-49 as a promising pan-EGFR inhibitor, currently in phase 1 clinical trials (CTR20212743).