Development of an FKBP12-recruiting Chemical-Induced Proximity DNA-Encoded Library and its application in the discovery of an autophagy potentiator

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 the first 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, and identified a compound that stabilizes the variant protein against Caspase-3 cleavage in a FKBP12-independent manner. We demonstrate in cellular models that this compound potentiates autophagy, reverses the xenophagy defects, and increases cytokine secretion characteristic of ATG16L1 T300A. This study  provides a platform to access new chemical space for CIP design to achieve novel therapeutic modalities guided by human genetics.