Receptor Interacting Protein Kinase 1 (RIPK1) plays a crucial role in regulating necroptosis and inflammation and the potential therapeutic benefits of RIPK1 inhibitors are being investigated in several clinical trials.^{1 ,2} We will describe the discovery and optimization of a new series of highly potent and selective RIPK1 inhibitors, that were identified by combining structure-based approaches, free-energy perturbation (FEP+) and state-of-the-art machine learning approaches for property predictions. Using X-ray crystallography, we could confirm that the inhibitors bind as allosteric type III inhibitors, thereby not contacting the kinase hinge region. We will illustrate how a C(sp3)-C(sp2) photochemical transformation was a key enabler for the efficient SAR exploration and profile optimization.

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.