Proteomics

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Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders


ABSTRACT: Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics1-3. Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs4-6. The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism, which we term “template-assisted covalent modification”. We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). BRD4BD2, in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 Å cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4BD2 have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16Cys58 covalent modification. Systematic mutagenesis of both DCAF16 and BRD4BD2 revealed that the loop conformation around BRD4His437, rather than specific side chains, is critical for BD2 selectivity. Supporting a general applicability, we find that a subset of compounds leads to a drug-induced GAK-BRD4 interaction stabilized by covalent modification of GAK. Together our work establishes “template-assisted covalent modification” as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Fischer  

LAB HEAD: Eric Fischer

PROVIDER: PXD047137 | Pride | 2024-08-09

REPOSITORIES: Pride

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Template-assisted covalent modification underlies activity of covalent molecular glues.

Li Yen-Der YD   Ma Michelle W MW   Hassan Muhammad Murtaza MM   Hunkeler Moritz M   Teng Mingxing M   Puvar Kedar K   Rutter Justine C JC   Lumpkin Ryan J RJ   Sandoval Brittany B   Jin Cyrus Y CY   Schmoker Anna M AM   Ficarro Scott B SB   Cheong Hakyung H   Metivier Rebecca J RJ   Wang Michelle Y MY   Xu Shawn S   Byun Woong Sub WS   Groendyke Brian J BJ   You Inchul I   Sigua Logan H LH   Tavares Isidoro I   Zou Charles C   Tsai Jonathan M JM   Park Paul M C PMC   Yoon Hojong H   Majewski Felix C FC   Sperling Haniya T HT   Marto Jarrod A JA   Qi Jun J   Nowak Radosław P RP   Donovan Katherine A KA   Słabicki Mikołaj M   Gray Nathanael S NS   Fischer Eric S ES   Ebert Benjamin L BL  

Nature chemical biology 20240729 12


Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans-labeling covalent molecular glue mechanism, termed 'template-assisted covalent modification'. We identified a new series of BRD4 molecular glue degraders that recruit CUL4<sup>DCAF16</sup> ligase to the se  ...[more]

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