{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:58:15Z","timestamp":1793041095767,"version":"4.5.0"},"reference-count":48,"publisher":"American Chemical Society (ACS)","issue":"37","license":[{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R15GM071388"],"award-info":[{"award-number":["R15GM071388"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000997","name":"Arnold and Mabel Beckman Foundation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100000997","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>An intriguing challenge of drug discovery is targeting pathogenic mutant proteins that differ from their wild-type counterparts by only a single amino acid. In particular, pathogenic cysteine mutations afford promising opportunities for mutant-specific drug discovery, due to the unique reactivity of cysteine\u2019s sulfhydryl-containing side chain. Here we describe the first directed discovery effort targeting a pathogenic cysteine mutant of a protein tyrosine phosphatase (PTP), namely Y279C Src-homology-2-containing PTP 2 (SHP2), which has been causatively linked to the developmental disorder Noonan syndrome with multiple lentigines (NSML). Through a screen of commercially available compounds that contain cysteine-reactive functional groups, we have discovered a small-molecule inhibitor of Y279C SHP2 (compound 99; IC50 \u2248 6 \u03bcM) that has no appreciable effect on the phosphatase activity of wild-type SHP2 or that of other homologous PTPs (IC50 \u226b 100 \u03bcM). Compound 99 exerts its specific inhibitory effect through irreversible engagement of Y279C SHP2\u2019s pathogenic cysteine residue in a manner that is time-dependent, is substrate-independent, and persists in the context of a complex proteome. To the best of our knowledge, 99 is the first specific ligand of a disease-causing PTP mutant to be identified. This study therefore provides both a starting point for the development of NSML-directed therapeutic agents and a precedent for the identification of mutant-specific inhibitors of other pathogenic PTP mutants.<\/jats:p>","DOI":"10.1021\/acs.biochem.0c00471","type":"journal-article","created":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T19:18:18Z","timestamp":1598987898000},"page":"3498-3507","source":"Crossref","is-referenced-by-count":7,"title":["Targeting a Pathogenic Cysteine Mutation: Discovery\nof a Specific Inhibitor of Y279C SHP2"],"prefix":"10.1021","volume":"59","author":[{"given":"Jenny Y.","family":"Kim","sequence":"first","affiliation":[{"name":"Amherst College , , , ,","place":["Amherst, Massachusetts, United States, 01002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bailey A.","family":"Plaman","sequence":"additional","affiliation":[{"name":"Amherst College , , , ,","place":["Amherst, Massachusetts, United States, 01002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8394-280X","authenticated-orcid":true,"given":"Anthony C.","family":"Bishop","sequence":"additional","affiliation":[{"name":"Amherst College , , , ,","place":["Amherst, Massachusetts, United States, 01002"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,9,1]]},"reference":[{"key":"2026090213394080700_cit1","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1038\/nrd3410","article-title":"The resurgence of covalent\ndrugs","volume":"10","author":"Singh","year":"2011","journal-title":"Nat. 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Chem."},{"key":"2026090213394080700_cit5","doi-asserted-by":"publisher","first-page":"2617","DOI":"10.1039\/C9CS00720B","article-title":"Advances\nin covalent kinase inhibitors","volume":"49","author":"Abdeldayem","year":"2020","journal-title":"Chem. Soc. Rev."},{"key":"2026090213394080700_cit6","doi-asserted-by":"publisher","first-page":"4372","DOI":"10.1002\/anie.201707875","article-title":"The cysteinome of protein\nkinases as a target in drug development","volume":"57","author":"Chaikuad","year":"2018","journal-title":"Angew.\nChem., Int. Ed."},{"key":"2026090213394080700_cit7","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.cbpa.2015.11.004","article-title":"Covalent targeting of acquired cysteines\nin cancer","volume":"30","author":"Visscher","year":"2016","journal-title":"Curr. Opin. Chem. Biol."},{"key":"2026090213394080700_cit8","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1038\/nature12796","article-title":"K-Ras(G12C)\ninhibitors allosterically control GTP affinity and effector interactions","volume":"503","author":"Ostrem","year":"2013","journal-title":"Nature"},{"key":"2026090213394080700_cit9","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/s41586-019-1694-1","article-title":"The clinical KRAS(G12C)\ninhibitor AMG 510 drives anti-tumour immunity","volume":"575","author":"Canon","year":"2019","journal-title":"Nature"},{"key":"2026090213394080700_cit10","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1021\/acs.jmedchem.9b01180","article-title":"Discovery\nof a covalent inhibitor of KRAS(G12C) (AMG 510) for the treatment\nof solid tumors","volume":"63","author":"Lanman","year":"2020","journal-title":"J. Med. Chem."},{"key":"2026090213394080700_cit11","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1086\/499925","article-title":"Diversity\nand functional consequences of germline and somatic PTPN11 mutations\nin human disease","volume":"78","author":"Tartaglia","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"2026090213394080700_cit12","doi-asserted-by":"publisher","first-page":"27066","DOI":"10.1074\/jbc.M112.350231","article-title":"Counteracting effects operating on Src homology 2 domain-containing\nprotein-tyrosine phosphatase 2 (SHP2) function drive selection of\nthe recurrent Y62D and Y63C substitutions in Noonan syndrome","volume":"287","author":"Martinelli","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2026090213394080700_cit13","doi-asserted-by":"publisher","first-page":"10472","DOI":"10.1074\/jbc.M113.450023","article-title":"Structural and mechanistic\ninsights into LEOPARD syndrome-associated SHP2 mutations","volume":"288","author":"Yu","year":"2013","journal-title":"J. Biol. Chem."},{"key":"2026090213394080700_cit14","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/j.ejmg.2015.08.005","article-title":"SHP2 sails\nfrom physiology to pathology","volume":"58","author":"Tajan","year":"2015","journal-title":"Eur. J. Med. Genet."},{"key":"2026090213394080700_cit15","doi-asserted-by":"publisher","first-page":"112117","DOI":"10.1016\/j.ejmech.2020.112117","article-title":"Therapeutic\npotential of targeting\nSHP2 in human developmental disorders and cancers","volume":"190","author":"Shen","year":"2020","journal-title":"Eur. J. Med. 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Cell Biol."},{"key":"2026090213394080700_cit22","doi-asserted-by":"publisher","first-page":"567","DOI":"10.2174\/1568009614666140717105001","article-title":"Structure,\nfunction, and pathogenesis of SHP2 in developmental\ndisorders and tumorigenesis","volume":"14","author":"Huang","year":"2014","journal-title":"Curr. Cancer Drug\nTargets"},{"key":"2026090213394080700_cit23","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1159\/000342251","article-title":"LEOPARD syndrome: Clinical features\nand gene mutations","volume":"3","author":"Marti\u0301nez-Quintana","year":"2012","journal-title":"Mol. Syndromol."},{"key":"2026090213394080700_cit24","doi-asserted-by":"publisher","first-page":"4136","DOI":"10.1021\/bi5002695","article-title":"Molecular basis of gain-of-function\nLEOPARD syndrome-associated SHP2Mutations","volume":"53","author":"Yu","year":"2014","journal-title":"Biochemistry"},{"key":"2026090213394080700_cit25","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/1472-6807-14-10","article-title":"Structural\ninsights into Noonan\/LEOPARD syndrome-related\nmutants of protein-tyrosine phosphatase SHP2 (PTPN11)","volume":"14","author":"Qiu","year":"2014","journal-title":"BMC Struct. Biol."},{"key":"2026090213394080700_cit26","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1093\/hmg\/ddn336","article-title":"Phosphatase-defective\nLEOPARD syndrome mutations in PTPN11 gene have gain-of-function effects\nduring Drosophila development","volume":"18","author":"Oishi","year":"2009","journal-title":"Hum. Mol. 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Chem."},{"key":"2026090213394080700_cit37","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1021\/acs.jpclett.6b02894","article-title":"Extraction\nof thermodynamic parameters of protein unfolding using parallelized\ndifferential scanning fluorimetry","volume":"8","author":"Wright","year":"2017","journal-title":"J. Phys.\nChem. Lett."},{"key":"2026090213394080700_cit38","doi-asserted-by":"publisher","first-page":"9593","DOI":"10.1021\/acs.jmedchem.9b01019","article-title":"Protein stability effects in aggregate-based enzyme\ninhibition","volume":"62","author":"Torosyan","year":"2019","journal-title":"J. Med. Chem."},{"key":"2026090213394080700_cit39","doi-asserted-by":"publisher","first-page":"4265","DOI":"10.1021\/jm030266r","article-title":"A specific mechanism\nof nonspecific inhibition","volume":"46","author":"McGovern","year":"2003","journal-title":"J. Med. 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Biol."},{"key":"2026090213394080700_cit44","doi-asserted-by":"publisher","first-page":"8171","DOI":"10.1021\/bi000319w","article-title":"Structural\nbasis of plasticity in protein tyrosine phosphatase 1B substrate recognition","volume":"39","author":"Sarmiento","year":"2000","journal-title":"Biochemistry"},{"key":"2026090213394080700_cit45","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/B978-0-12-405881-1.00008-2","article-title":"Redox regulation of protein tyrosine phosphatases:\nmethods for kinetic analysis of covalent enzyme inactivation","volume":"528","author":"Parsons","year":"2013","journal-title":"Methods Enzymol."},{"key":"2026090213394080700_cit46","doi-asserted-by":"publisher","first-page":"8251","DOI":"10.1021\/ja711125p","article-title":"Aryl vinyl sulfonates\nand sulfones as active site-directed and mechanism-based probes for\nprotein tyrosine phosphatases","volume":"130","author":"Liu","year":"2008","journal-title":"J. Am. Chem.\nSoc."},{"key":"2026090213394080700_cit47","doi-asserted-by":"publisher","first-page":"15763","DOI":"10.1021\/acsomega.8b02200","article-title":"The allosteric\nsite on SHP2\u2019s protein tyrosine phosphatase domain is targetable\nwith druglike small molecules","volume":"3","author":"Marsh-Armstrong","year":"2018","journal-title":"ACS Omega"},{"key":"2026090213394080700_cit48","doi-asserted-by":"publisher","first-page":"3326","DOI":"10.1021\/acs.biochem.8b00315","article-title":"The taxonomy of covalent\ninhibitors","volume":"57","author":"Tuley","year":"2018","journal-title":"Biochemistry"}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.biochem.0c00471","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/59\/37\/3498\/66944737\/acs.biochem.0c00471.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/59\/37\/3498\/66944737\/acs.biochem.0c00471.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:39:47Z","timestamp":1788370787000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/59\/37\/3498\/476199\/Targeting-a-Pathogenic-Cysteine-Mutation-Discovery"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,1]]},"references-count":48,"journal-issue":{"issue":"37","published-online":{"date-parts":[[2020,9,1]]},"published-print":{"date-parts":[[2020,9,22]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.biochem.0c00471","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,1]]}}}