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We introduce kinetic fingerprints as a mechanistically informative tool to guide kinase inhibitor design and predict clinical performance. Profiling 172 compounds across multiple KIT conformations, including the oncogenic D816V mutation, show that prolonged residence time determines therapeutic success, while mutations accelerating dissociation rates (\n                    <jats:italic>k<\/jats:italic>\n                    <jats:sub>off<\/jats:sub>\n                    ) drive resistance, positioning\n                    <jats:italic>k<\/jats:italic>\n                    <jats:sub>off<\/jats:sub>\n                    as a robust predictor of clinical failure. Beyond efficacy and resistance, kinetic signatures map molecular behavior: fast\u2010associating scaffolds engage readily populated KIT states, slow binders overcome conformational barriers like juxtamembrane repositioning, and extended residence times highlight ligands stabilizing regulatory elements (G\u2010loop and regulatory spine). Kinetic profiling further unveils mechanisms invisible to conventional methods, such as drug\u2010induced kinase degradation, and exposes selectivity dimensions beyond affinity: avapritinib exhibits durable KIT D816V engagement yet transient off\u2010target binding. Our findings redefine the evaluation of KIT inhibitors, establishing a framework for rational, kinetics\u2010guided drug discovery in KIT\u2010driven cancers.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70331","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T02:39:37Z","timestamp":1780540777000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Kinetic Fingerprints as Mechanistic and Clinical Roadmaps Across KIT Activation States"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9990-1214","authenticated-orcid":false,"given":"Ana","family":"Corrionero","sequence":"first","affiliation":[{"name":"Enzymlogic Qube Technology Park  Madrid Spain"},{"name":"Department of Biotechnology\u2010Plant Biology, School of Agricultural, Food and Biosystems Engineering Universidad Polit\u00e9cnica de Madrid  Madrid 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