Modern Computational Design Meets Late-Stage Functionalization: A New Class of RIPK1 Inhibitors

Speakers:

Hans Matter and Maria Méndez Pérez (Sanofi)
Tim Knehans (Schrödinger)

Abstract:

Receptor interacting protein kinase 1 (RIPK1) plays a crucial role in regulating cell homeostasis by integrating inflammatory and cell death signaling pathways.^1,2 Given its central position in multiple disease-relevant cascades, selective RIPK1 inhibitors with optimized pharmacokinetic properties represent promising therapeutic agents. This work details our comprehensive approach to designing a novel series of potent and selective RIPK1 inhibitors. Our discovery journey began with a structure-based hit finding strategy that combined scaffold hopping techniques with free energy perturbation (FEP) calculations, yielding an initial novel chemical scaffold. Subsequent optimization employed generative artificial intelligence algorithms alongside traditional structure-based design principles to develop the distinctive aryl-cyclobutyl motif. Detailed analysis of multiple X-ray co-crystals structures informed a second strategic rescaffolding effort specifically aimed at enhancing cellular activity, which successfully led to the innovative cyclobutyl-pyrazolopiperidinone series. To accelerate SAR exploration around the critical cyclobutyl group, we implemented late-stage photochemistry methods that efficiently identified high-potency aryl decorations. Further refinement utilized WaterMap technology and additional FEP calculations to optimize interactions within a secondary binding subpocket. Throughout the design process, we integrated predictions from an extensive panel of in-house in silico ADMET models to prioritize compounds with favorable overall profiles. The synergistic combination of these computational approaches with efficient synthetic chemistry ultimately delivered a compound with comprehensive candidate-like properties suitable for advanced development.

Literature: [1] Zhang. Y. et al. Eur. J. Med. Chem. 2024, 265, 116123. Lessene, G. et al. J. Med. Chem. 2023, 66, 2361. [2] He, S., Wang, X. RIP kinases as modulators of inflammation and immunity. Nat Immunol 2018, 19, 912.