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FGFR4 is recognized as a promising target to treat HCC. Currently, all FGFR covalent inhibitors target one of the two cysteines (Cys477 and Cys552). Here, we designed and synthesized a dual-warhead covalent FGFR4 inhibitor,\n                    <jats:bold>CXF-009<\/jats:bold>\n                    , targeting Cys477 and Cys552 of FGFR4. We report the cocrystal structure of FGFR4 with\n                    <jats:bold>CXF-009<\/jats:bold>\n                    , which exhibits a dual-warhead covalent binding mode.\n                    <jats:bold>CXF-009<\/jats:bold>\n                    exhibited stronger selectivity for FGFR4 than FGFR1-3 and other kinases. CXF-009 can also potently inhibit the single cystine mutants, FGFR4(C477A) and FGFR4(C552A), of FGFR4. In summary, our study provides a dual-warhead covalent FGFR4 inhibitor that can covalently target two cysteines of FGFR4.\n                    <jats:bold>CXF-009<\/jats:bold>\n                    , to our knowledge, is the first reported inhibitor that forms dual-warhead covalent bonds with two cysteine residues in FGFR4.\n                    <jats:bold>CXF-009<\/jats:bold>\n                    also has the potential to overcome drug induced resistant FGFR4 mutations and might serve as a lead compound for future anticancer drug discovery.\n                  <\/jats:p>","DOI":"10.1038\/s42004-022-00657-9","type":"journal-article","created":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T07:04:45Z","timestamp":1647500685000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Structure-based design of a dual-warhead covalent inhibitor of FGFR4"],"prefix":"10.1038","volume":"5","author":[{"given":"Xiaojuan","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiliang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianmeng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyan","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitong","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingzhi","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2072-2169","authenticated-orcid":false,"given":"Hudie","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3920-9878","authenticated-orcid":false,"given":"Longying","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4263-6579","authenticated-orcid":false,"given":"Guangyu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8139-6892","authenticated-orcid":false,"given":"Yongheng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,17]]},"reference":[{"key":"657_CR1","doi-asserted-by":"publisher","first-page":"2905","DOI":"10.1021\/acs.jmedchem.8b01531","volume":"62","author":"X Lu","year":"2019","unstructured":"Lu, X., Chen, H., Patterson, A. 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