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Herein, we report the discovery of a first-in-class chemotype 2-(alkylsulfonamido)thiazol-4-yl)acetamides that act as pan-selective inhibitors of cytidine 5'-triphosphate synthetase (CTPS1/2), critical enzymes in the

Molecular glue degraders are compact, low molecular weight molecules that can efficiently induce specific and potent degradation of a target protein. This class of degraders function by inducing interactions between a target of interest and a ubiquitin-ligase, either by stabilization of weak pre-existing interactions, or by generation of entirely novel interactions. These molecules offer significant opportunity beyond heterobifunctional degraders such as PROTACs, not least in terms of improved molecular properties. However, beyond the IMID molecular glues, typified by thalidomide, pomalidomide and lenalidomide, novel molecular glue chemotypes remain scarce. To address this need, we have developed biophysics-based molecular glue screening platform, exploiting our internal, high quality fragment library and proximity-based screening platforms to rapidly identify promising new molecular glues for further optimization. A potential advantage of utilizing cell-free biophysical systems is the opportunity to select both the target and the desired ligase, opening up for development of degraders that capitalize upon differential expression of ligases in different tissues. As proof of concept, we have applied this platform to find new molecular glues to degrade CK1α. This Ser/Thr kinase has been found to be over-expressed in metastatic colorectal cancer, and this over-expression correlates with poor overall survival. The kinase has also been implicated as an oncogenic driver in tumors such as B-Cell lymphomas and non-Hodgkin lymphomas, suggesting a potential therapeutic application for novel CK1α molecular glues. Utilizing known IMID-derived molecular glues between CK1α and CRBN as benchmark controls, we identified several non-IMID derived chemotypes as tentative stabilizers of the CRBN/CK1α interaction. Further studies on these novel candidate degrader templates are now underway. Citation Format: Yujia Zhang, Jessica Bates, Benoit Gourdet, Louise Birch, Philip Addis, Roland Hjerpe, Allan M. Jordan. Beyond cereblon IMIDs - biophysics-based discovery of novel molecular glue chemotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3429.

Many proteins undergo small side chain or even backbone movements on binding of different ligands into the same protein structure. This is known as induced fit and is potentially problematic for virtual screening of databases against protein targets. In this report we investigate the limits of the rigid protein approximation used by the docking program, GOLD, through cross-docking using protein structures of influenza neuraminidase. Neuraminidase is known to exhibit small but significant induced fit effects on ligand binding. Some neuraminidase crystal structures caused concern due to the bound ligand conformation and GOLD performed poorly on these complexes. A 'clean' set, which contained unique, unambiguous complexes, was defined. For this set, the lowest energy structure was correctly docked (i.e. RMSD1.5 A away from the crystal reference structure) in 84% of proteins, and the most promiscuous protein (1mwe) was able to dock all 15 ligands accurately including those that normally required an induced fit movement. This is considerably better than the 70% success rate seen with GOLD against general validation sets. Inclusion of specific water molecules involved in water-mediated hydrogen bonds did not significantly improve the docking performance for ligands that formed water-mediated contacts but it did prevent docking of ligands that displaced these waters. Our data supports the use of a single protein structure for virtual screening with GOLD in some applications involving induced fit effects, although care must be taken to identify the protein structure that performs best against a wide variety of ligands. The performance of GOLD was significantly better than the GOLD implementation of ChemScore and the reasons for this are discussed. Overall, GOLD has shown itself to be an extremely good, robust docking program for this system.