Abstract
ABSTRACT
The epidermal growth factor receptor (EGFR) is a validated therapeutic target for EGFR‐mutant non‐small cell lung cancer (NSCLC) and colorectal cancer, yet secondary T790M/C797S mutations and mesenchymal–epithelial transition factor (MET) amplification confer profound resistance to first‐, second‐, and third‐generation EGFR tyrosine kinase inhibitors (TKIs). Indole hybrids integrate indole cores (including azaindoles and fused indoles) with diverse pharmacophores to achieve multi‐site binding within the EGFR ATP pocket, conferring higher selectivity toward mutant EGFR than mono‐indole scaffolds. This review systematically summarizes indole‐based EGFR hybrids reported from 2021 to date into three categories: Phase I/II clinical candidates (
1
,
10
), C797S‐resistant preclinical leads (
11a
,
14a
,
34
,
48a
, and
50a
), and structurally diversified analogs with favorable blood–brain barrier (BBB) permeability and low systemic toxicity. Optimized indole hybrids exhibit prominent advantages over commercial TKIs, including enhanced binding affinity toward mutant EGFR, optimized pharmacokinetic profiles, minimized off‐target effects, and the capacity to suppress compensatory oncogenic signals. We comprehensively dissect their binding modes, structure–activity relationships (SARs), in vitro/in vivo anticancer activities, and pharmacological features, and summarize critical substituent optimization rules for overcoming resistance. This work establishes a systematic structural basis for rational development of next‐generation indole EGFR inhibitors against refractory EGFR‐driven malignancies.