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. 2023 Jul 26;8(31):27819–27844. doi: 10.1021/acsomega.3c00332

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© 2023 The Authors. Published by American Chemical Society

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Paradoxical activation. Note: Mechanism of autoinhibition: (1) In this case, inhibition of BRAF in the presence of a mutant or growth factor-activated RAS leads to abrogation of BRAF autoinhibition, so that it homodimerizes with BRAF and becomes hyperactivated. Conformational changes: (2, 3) At low doses, the drug binds only one RAF protomer and causes the other to transactivate. (4) At high doses, it binds to and inhibits both RAF dimers, effectively knocking down the signaling complex.