Abstract
Molecular glue degraders (MGDs) are small molecules that facilitate proximity between a target protein and an E3 ubiquitin ligase thereby inducing target protein degradation. Glutarimide-containing compounds are MGDs that bind to cereblon (CRBN) and recruit neosubstrates. Through explorative synthesis of a glutarimide-based library, we discovered a series of molecules that induce casein kinase 1 alpha (CK1α) degradation. By scaffold hopping and rational modification of the chemical scaffold, we identified an imidazo[1,2-a]pyrimidine compound that induces potent and selective CK1α degradation. A structure-activity relationship study of the lead compound, QXG-6442, identified the structural features that contribute to degradation potency and selectivity compared to other frequently observed neosubstrates. The glutarimide library screening and structure activity relationship medicinal chemistry approach we employed is generally useful for developing new molecular glue degraders towards new targets of interest.
Competing Interest Statement
K.A.D receives or has received consulting fees from Neomorph Inc. and Kronos Bio. E.S.F. is a founder, scientific advisory board (SAB) member, and equity holder of Civetta Therapeutics, Proximity Therapeutics, Stelexis BioSciences, and Neomorph, Inc. (also board of directors). he is an equity holder and SAB member for Avilar Therapeutics, Photys Therapeutics, and Ajax Therapeutics and an equity holder in Lighthorse Therapeutics, CPD4 and Anvia Therapeutics. E.S.F. is a consultant to Novartis, EcoR1 Capital, Odyssey and Deerfield. the Fischer lab receives or has received research funding from Deerfield, Novartis, Ajax, Interline, Bayer and Astellas. N.S.G. is a founder, science advisory board member (SAB) and equity holder in Syros, C4, Allorion, Lighthorse, Voronoi, Inception, Matchpoint, RedTree ventures, Shenandoah (board member), Larkspur (board member) and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield, Springworks, Interline and Sanofi. All other authors declare no competing interests.
Footnotes
We uploaded an incorrect version of Figure 3, which was identical to Figure 2. This has now been corrected.