Discovery of molecular glues that bind FKBP12 and novel targets using DNA-barcoded libraries

FKBP公司 计算生物学 DNA 溴尿嘧啶 化学 药物发现 生物化学 分子生物学 生物 组蛋白
作者
Trevor A. Zandi,M.J. Romanowski,Jessica S. Viscomi,Zher Yin Tan,Bingqi Tong,Simone Bonazzi,Frédéric J. Zécri,Stuart L. Schreiber,Gregory A. Michaud
标识
DOI:10.1101/2024.12.09.627499
摘要

ABSTRACT Molecular glues are small molecules that engage their target and presenter proteins cooperatively. FKBP12 molecular glues (FK506 and rapamycin) were discovered several decades ago and have been used clinically, but our understanding of the breadth of FKBP12 molecular glues and targets has yet to be fully revealed. To identify novel targets of FKBP12 molecular glues, we constructed and screened a multi-million- member non-macrocyclic FKBP12-ligand DNA-encoded library using 25 structurally distinct proteins. Synthesis and validation of selected hits in biophysical and cell-based assays confirm FKBP12-dependent molecular-glue recruitment to bromodomain-containing protein 9 (BRD9) and quinoid dihydropteridine reductase (QDPR). One glue showed no measurable binding to QDPR alone but had appreciable binding in the presence of FKBP12 using either purified proteins or intact cells. The sites of recruitment were characterized with mutational analysis, competition-based methods and X-ray crystallography. The results of this study confirm that FKBP12-binding DELs can yield novel molecular glues generating highly selective FKBP12-target protein interactions.

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