Schrödinger デジタル創薬セミナー: Into the Clinic ~計算化学がもたらす創薬プロセスの変貌~


Goran Krilov
Senior Director, Schrodinger Therapeutics Group


Mucosa-associated Lymphoid Tissue Lymphoma Translocation Protein 1 (MALT1) is a genetically validated target for the treatment of diseases associated with lymphocyte regulation. Unlike first generation inhibitors, centered on large peptidomimetics targeting the protease domain, second generation inhibitors targeting an allosteric region at the interface of the caspase-like and Ig3 domains are much more promising. Still, significant challenges remain in optimizing properties such as permeability, efflux, and solubility, while maintaining on-target potency. Harnessing the full potential of the Schrödinger platform which combines rigorous physics-based modeling with machine learning (ML), predictive ADMET models, and data analytics to search and triage a chemical space, we were able to rapidly identify multiple novel potent series. Subsequent in-silico multi parameter optimization (MPO) campaign quickly identified SGR-1505, a potential best-in-class MALT1 inhibitor with balanced properties and on-target activity, within 10 months of the start of the project and having synthesized only 129 compounds. SGR-1505 demonstrates strong positive effects in patient-derived B-cell tumor models both as a single agent as well as in combination with existing standard of care, and is currently progressing through Phase I clinical trials.