6UUO

Crystal structure of BRAF kinase domain bound to the PROTAC P4B

6UUO の概要

• エントリーDOI: 10.2210/pdb6uuo/pdb
• 分子名称: 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)
• 機能のキーワード: complex, protac, signaling, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65667.19

構造登録者

Maisonneuve, P.,Posternak, G.,Kurinov, I.,Sicheri, F. (登録日: 2019-10-30, 公開日: 2020-06-03, 最終更新日: 2023-10-11)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.288 Å)