molecules of the month


mut. BRAF sel. heterobifunctional degrader

efficacy in xenograft at 50 mg/kg IP BID

VHL-based degrader from vemurafenib

Nat. Comm., Feb. 10, 2021

Yale University, New Haven, CT

1 min read

13. The Yale BRAF-targeting PROTAC SJF-0628 is a VHL-based heterobifunctional degrader with in vivo activity in a xenograft model (50 mg/kg BID IP). Though mutant BRAF is a well-validated target, drugging mutant forms selectively over wild-type continues to be a challenge. It had been hypothesized that modalities such as targeted degradation might be a viable strategy to achieve functional selectivity for mutant forms of BRAF. Interestingly, the authors show here that BRAFWT is degraded to a far lower extent due to a weaker ternary complex between the compound and E3 ligase in cells, despite lower selectivity of the parent BRAF inhibitor, vemurafenib. However, under different cellular contexts, the authors show that wild-type still appears to be degraded, which may still…

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