Mutant-selective degradation by BRAF-targeting PROTACs

Shanique Alabi, Saul Jaime-Figueroa, Zhan Yao, Yijun Gao, John Hines, Kusal T. G. Samarasinghe, Lea Vogt, Neal Rosen and Craig M. Crews ()
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Shanique Alabi: Department of Pharmacology
Saul Jaime-Figueroa: Molecular, Cellular, and Developmental Biology, Yale University
Zhan Yao: Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center
Yijun Gao: Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center
John Hines: Molecular, Cellular, and Developmental Biology, Yale University
Kusal T. G. Samarasinghe: Molecular, Cellular, and Developmental Biology, Yale University
Lea Vogt: Molecular, Cellular, and Developmental Biology, Yale University
Neal Rosen: Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center
Craig M. Crews: Department of Pharmacology

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Over 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we achieve low nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAFWT is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAFWT sensitizes it to degradation. This study highlights the degree of selectivity achievable with degradation-based approaches by targeting mutant BRAF-driven cancers while sparing BRAFWT, providing an anti-tumor drug modality that expands the therapeutic window.

Date: 2021
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DOI: 10.1038/s41467-021-21159-7

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