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However, studies have shown that the HSP70 family is differentially regulated across cancers, and global targeting may produce unwanted toxicities. For this reason, our lab has focused on isoform\u2010selective targeting of HSP70s, including the endoplasmic reticulum\u2010resident HSP70, GRP78 (HSPA5 or BiP). GRP78 is a central component of protein homeostasis in the secretory system and is the principal regulator of the unfolded protein response (UPR). Here, we report the use of a direct\u2010to\u2010biology (D2B) strategy to optimize a dipeptide\u2010based scaffold that binds selectively to GRP78, relative to the other canonical HSP70s. We show that our lead compound,\n                    <jats:bold>12<\/jats:bold>\n                    , potently and selectively inhibits GRP78, binds to the substrate binding pocket, kills A549 lung cancer cells in 2D (grown as a monolayer) and 3D (grown as spheroids) cultures, engages GRP78 in cells, and that GRP78 inhibition is responsible for the mode of action. This work represents the first GRP78\u2010selective inhibitor that inhibits substrate binding.\n                  <\/jats:p>","DOI":"10.1002\/anie.202523960","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T09:39:19Z","timestamp":1776937159000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["GRP78 Selective Inhibitors From a Direct\u2010to\u2010Biology Strategy"],"prefix":"10.1002","volume":"65","author":[{"given":"Xiaoyi","family":"Zhu","sequence":"first","affiliation":[{"name":"College of Medicine Department of Pharmacology and Therapeutics Center For Inflammation Science and Systems Medicine The Herbert Wertheim UF Scripps Institute For Biomedical Innovation and Technology University of Florida  Jupiter Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlee A.","family":"Trindl","sequence":"additional","affiliation":[{"name":"College of Medicine 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Pharmacology and Therapeutics Center For Inflammation Science and Systems Medicine The Herbert Wertheim UF Scripps Institute For Biomedical Innovation and Technology University of Florida  Jupiter Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben N.","family":"Stansfield","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Center For Inflammation Science and Systems Medicine UF Scripps Institute For Biomedical Innovation and Technology  Jupiter Florida USA"},{"name":"Genetics Graduate Interdisciplinary Program University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aikseng","family":"Ooi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Center For Inflammation Science and Systems Medicine UF Scripps Institute For Biomedical Innovation and Technology  Jupiter Florida USA"},{"name":"Division of Hematology and Oncology Department of Medicine 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