{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T12:02:01Z","timestamp":1790596921884,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Aberrant activation of EGFR drives the progression of non-small-cell lung cancer (NSCLC). As one of the most prevalent driver genes in NSCLC, EGFR represents a critical therapeutic target for patients with NSCLC. In this study, we synthesized 2,4-pyrimidinediamine derivative ZX-3. Compared to its lead compound ceritinib, which has weak cytotoxicity for EGFR-driven NSCLC, ZX-3 exhibited potent cytotoxicity against EGFR-driven NSCLC. We further investigated the antitumor activity and mechanisms of ZX-3 both in vitro and in vivo. Through high-throughput target screening using RTK protein arrays and surface plasmon resonance (SPR) assays, it was demonstrated that ZX-3 reversibly targets the EGFR protein and inhibits its downstream PI3K\/AKT signaling pathway. In vitro experiments revealed that ZX-3 suppresses cell colony formation in H2228 cells, induces G1-phase cell cycle arrest, and promotes apoptosis. In in vivo xenograft studies, ZX-3 treatment significantly suppressed tumor growth without obvious toxicity. Collectively, ZX-3 represents a reversible EGFR inhibitor based on borylation modification and possesses favorable antitumor activity both in vitro and in vivo, offering a novel strategy for the subsequent development of EGFR-targeted inhibitors.<\/jats:p>","DOI":"10.3390\/molecules31193440","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:35:59Z","timestamp":1790595359000},"page":"3440","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel 2,4-Pyrimidinediamine Derivative as Potent EGFR Inhibitor for NSCLC Treatment"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7147-744X","authenticated-orcid":false,"given":"Shiqi","family":"Jia","sequence":"first","affiliation":[{"name":"University of Science and Technology of China, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Xiaolin","family":"Lv","sequence":"additional","affiliation":[{"name":"Changchun University of Science and Technology College of Optical and Electronic Information, Changchun 130114, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Jia","family":"Lv","sequence":"additional","affiliation":[{"name":"Changchun University of Science and Technology College of Optical and Electronic Information, Changchun 130114, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Yiran","family":"Wu","sequence":"additional","affiliation":[{"name":"iHuman Institute, ShanghaiTech University, Shanghai 201210, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"software","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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