6UUO

Crystal structure of BRAF kinase domain bound to the PROTAC P4B

Summary for 6UUO

• Entry DOI: 10.2210/pdb6uuo/pdb
• Descriptor: Serine/threonine-protein kinase B-raf, N-(3-{5-[(1-acetylpiperidin-4-yl)(methyl)amino]-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl}-2,4-difluorophenyl)propane-1-sulfonamide (3 entities in total)
• Functional Keywords: complex, protac, signaling, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 65667.19

Authors

Maisonneuve, P.,Posternak, G.,Kurinov, I.,Sicheri, F. (deposition date: 2019-10-30, release date: 2020-06-03, Last modification date: 2023-10-11)

Primary citation

Posternak, G.,Tang, X.,Maisonneuve, P.,Jin, T.,Lavoie, H.,Daou, S.,Orlicky, S.,Goullet de Rugy, T.,Caldwell, L.,Chan, K.,Aman, A.,Prakesch, M.,Poda, G.,Mader, P.,Wong, C.,Maier, S.,Kitaygorodsky, J.,Larsen, B.,Colwill, K.,Yin, Z.,Ceccarelli, D.F.,Batey, R.A.,Taipale, M.,Kurinov, I.,Uehling, D.,Wrana, J.,Durocher, D.,Gingras, A.C.,Al-Awar, R.,Therrien, M.,Sicheri, F.
Functional characterization of a PROTAC directed against BRAF mutant V600E.
Nat.Chem.Biol., 16:1170-1178, 2020

PubMed Abstract: The RAF family kinases function in the RAS-ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation and survival, enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAF(V600E) have shown great efficacy in the clinic, but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated. Here, we investigated a proteolysis-targeting chimera (PROTAC) approach to BRAF inhibition. The most effective PROTAC, termed P4B, displayed superior specificity and inhibitory properties relative to non-PROTAC controls in BRAF(V600E) cell lines. In addition, P4B displayed utility in cell lines harboring alternative BRAF mutations that impart resistance to conventional BRAF inhibitors. This work provides a proof of concept for a substitute to conventional chemical inhibition to therapeutically constrain oncogenic BRAF.

PubMed: 32778845
DOI: 10.1038/s41589-020-0609-7

Experimental method

X-RAY DIFFRACTION (3.288 Å)