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Currently approved rapidly accelerated fibrosarcoma (RAF) kinase inhibitors targeting oncogenic BRAF V600 mutations have shown remarkable efficacy in the clinic, but their therapeutic benefits are occasionally hampered by acquired resistance due to RAF dimerization\u2013dependent reactivation of the downstream MAPK pathway, which is known as paradoxical activation. There is also a concern that paradoxical activation of the MAPK pathway may trigger secondary cancer progression. In this study, we developed chimeric compounds, proteolysis targeting chimeras (PROTACs), that target BRAF<jats:sup>V600E<\/jats:sup> protein for degradation. CRBN(BRAF)\u201024, the most effective chimera, potently degraded BRAF<jats:sup>V600E<\/jats:sup> in a ubiquitin\u2010proteasome system (UPS)\u2010dependent manner and inhibited the proliferation of BRAF<jats:sup>V600E<\/jats:sup>\u2010driven cancer cells. In BRAF wild\u2010type cells, CRBN(BRAF)\u201024 induced neither BRAF<jats:sup>WT<\/jats:sup> degradation nor paradoxical activation of the MAPK pathway. Biochemical analysis revealed that CRBN(BRAF)\u201024 showed more potent and sustained suppression of MAPK signaling than a BRAF<jats:sup>V600E<\/jats:sup> inhibitor, PLX\u20108394, in BRAF<jats:sup>V600E<\/jats:sup>\u2010driven cancer cells. Targeted degradation of BRAF<jats:sup>V600E<\/jats:sup> by CRBN(BRAF)\u201024 could be a promising strategy to evade paradoxical activation of the RAF\u2010MAPK pathway.<\/jats:p>","DOI":"10.1111\/cas.15401","type":"journal-article","created":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T09:49:26Z","timestamp":1652780966000},"page":"2828-2838","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Development of a potent small\u2010molecule degrader against oncogenic <scp>BRAF<sup>V600E<\/sup><\/scp> protein that evades paradoxical <scp>MAPK<\/scp> activation"],"prefix":"10.1111","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0533-0610","authenticated-orcid":false,"given":"Nobumichi","family":"Ohoka","sequence":"first","affiliation":[{"name":"Division of Molecular Target and Gene Therapy Products National Institute of Health Sciences  Kawasaki Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Modality Research Laboratories, Biologics Division Daiichi Sankyo Co., Ltd.  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