Tan Zher Yin, Adade Joel K A, Gu Xiebin, Hecht Cody J S, Salcius Michael, Tong Bingqi, Liu Shuang, Hwang Seungmin, Zécri Frédéric J, Graham Daniel B, Schreiber Stuart L, Xavier Ramnik J
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cell Chem Biol. 2025 Mar 20;32(3):498-510.e35. doi: 10.1016/j.chembiol.2024.12.002. Epub 2025 Jan 2.
Chemical inducers of proximity (CIPs) are molecules that recruit one protein to another and introduce new functionalities toward modulating protein states and activities. While CIP-mediated recruitment of E3 ligases is widely exploited for the development of degraders, other therapeutic modalities remain underexplored. We describe a non-degrader CIP-DNA-encoded library (CIP-DEL) that recruits FKBP12 to target proteins using non-traditional acyclic structures, with an emphasis on introducing stereochemically diverse and rigid connectors to attach the combinatorial library. We deployed this strategy to modulate ATG16L1 T300A, which confers genetic susceptibility to Crohn's disease (CD), and identified a compound that stabilizes the variant protein against caspase-3 (Casp3) cleavage in a FKBP12-independent manner. We demonstrate in cellular models that this compound potentiates autophagy, and reverses the xenophagy defects as well as increased cytokine secretion characteristic of ATG16L1 T300A. This study provides a platform to access unexplored chemical space for CIP design to develop therapeutic modalities guided by human genetics.
邻近化学诱导剂（CIPs）是一类能将一种蛋白质招募到另一种蛋白质并引入新功能以调节蛋白质状态和活性的分子。虽然CIP介导的E3连接酶招募已被广泛用于开发降解剂，但其他治疗方式仍未得到充分探索。我们描述了一种非降解型CIP-DNA编码文库（CIP-DEL），它使用非传统的无环结构将FKBP12招募到靶蛋白上，重点是引入立体化学多样且刚性的连接子来连接组合文库。我们采用这种策略来调节ATG16L1 T300A，该突变赋予了克罗恩病（CD）遗传易感性，并鉴定出一种化合物，它能以不依赖FKBP12的方式稳定变异蛋白，使其免受半胱天冬酶-3（Casp3）的切割。我们在细胞模型中证明，这种化合物能增强自噬，并逆转ATG16L1 T300A所特有的异源吞噬缺陷以及细胞因子分泌增加的现象。这项研究提供了一个平台，用于探索CIP设计中未被探索的化学空间，以开发由人类遗传学指导的治疗方式。
