Protomer selectivity of type II RAF inhibitors within the RAS/RAF complex.
| Autor: | Vasta JD; Promega Corporation, Madison, WI, USA., Michaud A; Promega Corporation, Madison, WI, USA., Zimprich CA; Promega Corporation, Madison, WI, USA., Beck MT; Promega Corporation, Madison, WI, USA., Swiatnicki MR; Promega Corporation, Madison, WI, USA., Zegzouti H; Promega Corporation, Madison, WI, USA., Thomas MR; Promega Corporation, Madison, WI, USA., Wilkinson J; Promega Corporation, Madison, WI, USA., Crapster JA; Vibliome Therapeutics LLC, Bozeman, MT, USA. Electronic address: aaron.crapster@vibliome.com., Robers MB; Promega Corporation, Madison, WI, USA. Electronic address: matt.robers@promega.com. |
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| Jazyk: | angličtina |
| Zdroj: | Cell chemical biology [Cell Chem Biol] 2023 Nov 16; Vol. 30 (11), pp. 1354-1365.e6. Date of Electronic Publication: 2023 Aug 28. |
| DOI: | 10.1016/j.chembiol.2023.07.019 |
| Abstrakt: | RAF dimer inhibitors offer therapeutic potential in RAF- and RAS-driven cancers. The utility of such drugs is predicated on their capacity to occupy both RAF protomers in the RAS-RAF signaling complex. Here we describe a method to conditionally quantify drug-target occupancy at selected RAF protomers within an active RAS-RAF complex in cells. RAF target engagement can be measured in the presence or absence of any mutant KRAS allele, enabling the high-affinity state of RAF dimer inhibitors to be quantified in the cellular milieu. The intracellular protomer selectivity of clinical-stage type II RAF inhibitors revealed that ARAF protomer engagement, but not engagement of BRAF or CRAF, is commensurate with inhibition of MAPK signaling in various mutant RAS cell lines. Our results support a fundamental role for ARAF in mutant RAS signaling and reveal poor ARAF protomer vulnerability for a cohort of RAF inhibitors undergoing clinical evaluation. Competing Interests: Declaration of interests Authors on this manuscript are employed by Promega. Promega owns patents related to target engagement using BRET. (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.) |
| Databáze: | MEDLINE |
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