Discovery and preclinical evaluations of drug candidate DA-0157 capable of overcoming EGFR drug-resistant mutation C797S and EGFR/ALK co-mutations.

in European journal of medicinal chemistry by Peng He, Haiyan Li, Zhenyu Yang, Rui Zhang, Qijun Ye, Ta Deng, Wenwen Li, Shucheng He, Guangxin Dong, Zhou Yu, Yi Li

TLDR

  • A new small-molecule drug candidate, DA-0157, has been discovered and preclinically evaluated for its ability to overcome EGFR drug-resistant mutation C797S and EGFR/ALK co-mutations in NSCLC patients.
  • DA-0157 demonstrated excellent in vitro and in vivo efficacy, favorable pharmacokinetic properties, and safety profiles, making it a promising therapeutic agent for NSCLC patients.

Abstract

Activating mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are significant oncogenic drivers in non-small cell lung cancer (NSCLC) patients. Despite several approved EGFR and ALK inhibitors, drug-resistant mutations pose a major challenge. Especially, there is currently no approved EGFR inhibitors targeting the C797S mutation, a refractory mutation resistant to the third-generation EGFR inhibitors. Furthermore, an increasing number of patients with EGFR/ALK co-mutations have been identified in clinical practice, yet there are no effective therapeutic options available for them. In this study, we report the discovery and preclinical evaluations of a new small-molecule drug candidate, DA-0157, which is capable of overcoming EGFR drug-resistant mutation C797S and EGFR/ALK co-mutations. DA-0157 demonstrated excellent in vitro efficacy, significantly inhibiting various EGFRmutants resistant to the third-generation EGFR inhibitors, ALK rearrangements, and EGFR/ALK co-mutations. In vivo studies revealed that DA-0157 substantially inhibited tumor growth in the LD1-0025-200717 EGFRPDX model (40 mg/kg/d, TGI: 98.3 %), Ba/F3-EML-4-ALK-L1196 M CDX model (40 mg/kg/d, TGI: 125.2 %), and NCI-H1975 EGFR& NCI-H3122 (EML4-ALK) dual-side implantation CDX model (40 mg/kg/d, TGI: 89.5 % & 113.9 %). DA-0157 demonstrates favorable pharmacokinetic properties and safety. Currently, DA-0157 (DAJH-1050766) is undergoing Phase I/II clinical trials.

Overview

  • The study focuses on discovering a new small-molecule drug candidate, DA-0157, that can overcome EGFR drug-resistant mutation C797S and EGFR/ALK co-mutations in non-small cell lung cancer (NSCLC) patients.
  • DA-0157 was evaluated in vitro and in vivo against various EGFR mutants resistant to third-generation EGFR inhibitors, ALK rearrangements, and EGFR/ALK co-mutations.
  • The primary objective is to identify a novel therapeutic option for NSCLC patients with EGFR drug-resistant mutations or EGFR/ALK co-mutations, and DA-0157 is currently undergoing Phase I/II clinical trials.

Comparative Analysis & Findings

  • DA-0157 demonstrated excellent in vitro efficacy, significantly inhibiting various EGFR mutants resistant to third-generation EGFR inhibitors, ALK rearrangements, and EGFR/ALK co-mutations.
  • In vivo studies revealed that DA-0157 substantially inhibited tumor growth in three different models, including EGFR-PDX, Ba/F3-EML-4-ALK-L1196, and NCI-H1975 EGFR&NCI-H3122 (EML4-ALK) dual-side implantation.
  • DA-0157 exhibited favorable pharmacokinetic properties and safety profiles, indicating its potential as a promising therapeutic agent for NSCLC patients.

Implications and Future Directions

  • The discovery of DA-0157 provides a new therapeutic option for NSCLC patients with EGFR drug-resistant mutations or EGFR/ALK co-mutations, which could improve treatment outcomes and quality-of-life.
  • Further clinical evaluations, including Phase III trials and expanded patient populations, are necessary to fully understand the efficacy and tolerability of DA-0157 in NSCLC patients.
  • Researchers may also explore combining DA-0157 with other targeted therapies or immunotherapies to enhance treatment effectiveness and address potential resistance mechanisms.
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