Indole Hybrids: Emerging EGFR-Targeted Agents With Multifaceted Anticancer Properties (2021-Present).

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.