1. Template-assisted covalent modification underlies activity of covalent molecular glues.
- Author
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Li YD, Ma MW, Hassan MM, Hunkeler M, Teng M, Puvar K, Rutter JC, Lumpkin RJ, Sandoval B, Jin CY, Schmoker AM, Ficarro SB, Cheong H, Metivier RJ, Wang MY, Xu S, Byun WS, Groendyke BJ, You I, Sigua LH, Tavares I, Zou C, Tsai JM, Park PMC, Yoon H, Majewski FC, Sperling HT, Marto JA, Qi J, Nowak RP, Donovan KA, Słabicki M, Gray NS, Fischer ES, and Ebert BL
- Subjects
- Humans, Proteolysis, HEK293 Cells, Protein Binding, Models, Molecular, Bromodomain Containing Proteins, Transcription Factors metabolism, Transcription Factors chemistry, Cell Cycle Proteins metabolism, Cell Cycle Proteins chemistry
- Abstract
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
DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2 ). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4BD2 serves as a template to optimally orient the degrader for covalent modification of DCAF16Cys58 . This process stabilizes the formation of BRD4-degrader-DCAF16 ternary complex and facilitates BRD4 degradation. Supporting generalizability, we found that a subset of degraders also induces GAK-BRD4BD2 interaction through trans-labeling 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., Competing Interests: Competing interests: B.L.E. has received research funding from Celgene, Deerfield, Novartis and Calico Life Sciences and consulting fees from AbbVie. He is a member of the scientific advisory board (SAB) for and a shareholder of Neomorph, Inc., TenSixteen Bio, Skyhawk Therapeutics and Exo Therapeutics. E.S.F. is a founder, SAB member and equity holder of Civetta Therapeutics, Lighthorse Therapeutics, Proximity Therapeutics and Neomorph, Inc. (board of directors). He is an equity holder in and SAB member for Avilar Therapeutics and Photys Therapeutics and a consultant to Novartis, Sanofi, EcoR1 Capital and Deerfield. The Fischer laboratory receives or has received research funding from Deerfield, Novartis, Ajax, Interline and Astellas. N.S.G. is a founder, SAB member and equity holder in Syros, C4, Allorion, Lighthorse, Voronoi, Inception, Matchpoint, CobroVentures, GlaxoSmithKline, Larkspur (board member), Shenandoah (board member) and Soltego (board member). The Gray laboratory receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield, Springworks, Interline and Sanofi. M.S. has received research funding from Calico Life Sciences. K.A.D. receives or has received consulting fees from Kronos Bio and Neomorph, Inc. J.Q. is an equity holder of Epiphanes and Talus Bioscience and receives or has received research funding from Novartis. J.A.M. is a founder and equity holder of and advisor to Entact Bio, serves on the SAB of 908 Devices and receives or has received sponsored research funding from Vertex, AstraZeneca, Taiho, Springworks, TUO Therapeutics and Bruker. Y.-D.L. is currently employed by Leerink Partners. M.W.M. is currently employed by Novartis Venture Fund. K.P. is currently employed by AbbVie. R.J.L. is currently employed by Flagship Pioneering. B.J.G. is currently employed by Blueprint Medicines. I.Y. is currently employed by Matchpoint Therapeutics. The remaining authors declare no competing interests., (© 2024. The Author(s).)- Published
- 2024
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