{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T15:47:43Z","timestamp":1792079263002,"version":"4.4.0"},"reference-count":87,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["RSG-23-1038049-01-TBE"],"award-info":[{"award-number":["RSG-23-1038049-01-TBE"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30 CA013696"],"award-info":[{"award-number":["P30 CA013696"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Protein tyrosine kinases are important regulators of cell signaling, and aberrant kinase activity contributes to many human diseases, including cancers. All protein tyrosine kinases share a highly conserved ATP-binding pocket but diverge in their substrate-binding sites in order to mediate distinct signaling events. Many potent and efficacious ATP-competitive tyrosine kinase inhibitors have been developed; however, it remains challenging to achieve on-target selectivity across different kinases and target-specific disease mutants, given the high degree of conservation in the ATP-binding pocket. By contrast, the variable substrate-binding site offers an opportunity for selective inhibition, provided molecules can be targeted to this site. Here, we present a modular strategy to design selective, peptide-based covalent inhibitors of tyrosine kinases with a distinct binding mode from existing ATP-competitive inhibitors. Using Src kinase as a model system, we demonstrate that Src-selective reactivity can be achieved by first designing an optimized substrate peptide and then strategically positioning an electrophile on the peptide to target a nonconserved cysteine on the kinase. We show that substrate-derived covalent peptides can inhibit kinase activity, bind simultaneously with an ATP-competitive inhibitor, and even inhibit the activity of kinases bearing a common drug resistance mutation. We further explore the application of this approach to develop an inhibitor of the cancer-relevant fibroblast growth factor receptor 1 kinase that shows selectivity for an oncogenic mutant over the wild-type enzyme. Our modular strategy to generate selective covalent peptides targeting protein tyrosine kinases provides a promising framework for future chemical probe and drug development efforts.<\/jats:p>","DOI":"10.1021\/acschembio.6c00468","type":"journal-article","created":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T22:13:29Z","timestamp":1788128009000},"page":"2306-2321","source":"Crossref","is-referenced-by-count":0,"title":["Substrate-Derived Peptides for Selective Covalent Inhibition of Protein Tyrosine Kinases"],"prefix":"10.1021","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7141-7351","authenticated-orcid":true,"given":"Minhee","family":"Lee","sequence":"first","affiliation":[{"name":"Columbia University , , , ,","place":["New York, NY, United States, 10027"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C.","family":"Johns","sequence":"additional","affiliation":[{"name":"Columbia University , , , ,","place":["New York, NY, United States, 10027"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijing","family":"Wang","sequence":"additional","affiliation":[{"name":"Columbia University , , , ,","place":["New York, NY, United States, 10027"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devon A.","family":"Semoy","sequence":"additional","affiliation":[{"name":"Columbia University , , , ,","place":["New York, NY, United States, 10027"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1186-0626","authenticated-orcid":true,"given":"Neel H.","family":"Shah","sequence":"additional","affiliation":[{"name":"Columbia University , , , ,","place":["New York, NY, United States, 10027"]},{"name":"Columbia University , , , ,","place":["New York, NY, United States, 10032"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"issue":"5600","key":"2026101511062948000_cit1","doi-asserted-by":"publisher","first-page":"1912","DOI":"10.1126\/science.1075762","article-title":"The Protein Kinase Complement of the Human Genome","volume":"298","author":"Manning","year":"2002","journal-title":"Science"},{"issue":"11","key":"2026101511062948000_cit2","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/s41573-021-00252-y","article-title":"Trends in Kinase Drug Discovery: Targets, Indications and Inhibitor Design","volume":"20","author":"Attwood","year":"2021","journal-title":"Nat. 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