7Z76

Crystal structure of compound 10 in complex with the bromodomain of human SMARCA2 and pVHL:ElonginC:ElonginB

Summary for 7Z76

• Entry DOI: 10.2210/pdb7z76/pdb
• Related: 7Z6L
• Descriptor: Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (7 entities in total)
• Functional Keywords: protac, complex, bromodomain, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 57771.36

Authors

Bader, G.,Boettcher, J.,Wolkerstorfer, B. (deposition date: 2022-03-15, release date: 2022-09-14, Last modification date: 2024-01-31)

Primary citation

Kofink, C.,Trainor, N.,Mair, B.,Wohrle, S.,Wurm, M.,Mischerikow, N.,Roy, M.J.,Bader, G.,Greb, P.,Garavel, G.,Diers, E.,McLennan, R.,Whitworth, C.,Vetma, V.,Rumpel, K.,Scharnweber, M.,Fuchs, J.E.,Gerstberger, T.,Cui, Y.,Gremel, G.,Chetta, P.,Hopf, S.,Budano, N.,Rinnenthal, J.,Gmaschitz, G.,Mayer, M.,Koegl, M.,Ciulli, A.,Weinstabl, H.,Farnaby, W.
A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo.
Nat Commun, 13:5969-5969, 2022

PubMed Abstract: Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.

PubMed: 36216795
DOI: 10.1038/s41467-022-33430-6

Experimental method

X-RAY DIFFRACTION (1.32 Å)