{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:53:02Z","timestamp":1791359582782,"version":"4.3.1"},"reference-count":82,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The epidermal growth factor receptor (EGFR) is a validated therapeutic target for EGFR\u2010mutant non\u2010small cell lung cancer (NSCLC) and colorectal cancer, yet secondary T790M\/C797S mutations and mesenchymal\u2013epithelial transition factor (MET) amplification confer profound resistance to first\u2010, second\u2010, and third\u2010generation EGFR tyrosine kinase inhibitors (TKIs). Indole hybrids integrate indole cores (including azaindoles and fused indoles) with diverse pharmacophores to achieve multi\u2010site binding within the EGFR ATP pocket, conferring higher selectivity toward mutant EGFR than mono\u2010indole scaffolds. This review systematically summarizes indole\u2010based EGFR hybrids reported from 2021 to date into three categories: Phase I\/II clinical candidates (\n                    <jats:bold>1<\/jats:bold>\n                    ,\n                    <jats:bold>10<\/jats:bold>\n                    ), C797S\u2010resistant preclinical leads (\n                    <jats:bold>11a<\/jats:bold>\n                    ,\n                    <jats:bold>14a<\/jats:bold>\n                    ,\n                    <jats:bold>34<\/jats:bold>\n                    ,\n                    <jats:bold>48a<\/jats:bold>\n                    , and\n                    <jats:bold>50a<\/jats:bold>\n                    ), and structurally diversified analogs with favorable blood\u2013brain 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\u2010target effects, and the capacity to suppress compensatory oncogenic signals. We comprehensively dissect their binding modes, structure\u2013activity 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\u2010generation indole EGFR inhibitors against refractory EGFR\u2010driven malignancies.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70334","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:29:36Z","timestamp":1791358176000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Indole Hybrids: Emerging EGFR\u2010Targeted Agents With Multifaceted Anticancer Properties (2021\u2013Present)"],"prefix":"10.1002","volume":"359","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1368-0131","authenticated-orcid":false,"given":"Bin","family":"Zhang","sequence":"first","affiliation":[{"name":"Affiliated Zhumadian Central Hospital of Huanghuai University Zhumadian China"},{"name":"School of Chemistry and Pharmaceutical Engineering Huanghuai University Zhumadian China"},{"name":"Topfond Pharmaceutical Co. 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Zhumadian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Wang","sequence":"additional","affiliation":[{"name":"Affiliated Zhumadian Central Hospital of Huanghuai University Zhumadian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shifang","family":"Wen","sequence":"additional","affiliation":[{"name":"Affiliated Zhumadian Central Hospital of Huanghuai University Zhumadian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengqiao","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chemistry and Pharmaceutical Engineering Huanghuai University Zhumadian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Affiliated Zhumadian Central Hospital of Huanghuai University Zhumadian 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