Various BRAF kinase inhibitors were developed to treat cancers carrying the BRAF mutation. First-generation BRAF inhibitors could lead to paradoxical activation of the MAPK pathway, limiting their clinical usefulness. Here, we show the development of two series of BRAF-targeting PROTACs and demonstrate that the exchange of the inhibitor scaffold from vemurafenib to paradox-breaker ligands resulted in BRAF degraders that did not cause paradoxical ERK activation.
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