Refinement of Peptidomimetics toward MUR-2425: A Brain-Penetrant and Selective Caspase-2 Inhibitor with Enhanced Pharmacokinetics
Bernadette Vallaster, Lisa Forster, Merlin Bresinsky, Lukas Wirth, Jessica L. Fuller, Ke Shi, Ian P. Lapcinski, Peng Liu, Deepti Mudaliar, Alexander Hubmann, Jonas Daschner, Herwig Pongratz, Marlisa Ködel, Mu Yang, Karen H. Ashe, Michael A. Walters, Steffen PockesAbstract
Caspase-2 (Casp2) has emerged as a promising target for tau-associated neurodegenerative diseases, yet the development of potent, selective, and drug-like inhibitors remains challenging. Here, we report a systematic structure–activity relationship study of 80 novel covalent-reversible peptidomimetic Casp2 inhibitors, revealing key structural features of the Casp2 S2–S3 binding site and discovering (S)-2-methylindoline-2-carboxylic acid (2-Me-Idc) and quinaldic acid (Quin) as versatile and stable P5 scaffolds. One-step conversion of the aldehyde warhead into a nitrile remarkably enhanced selectivity while maintaning potency. The results culminate in MUR-2425 (87, (2-Me-Idc)(hE)VP*D-CN), a nanomolar Casp2 inhibitor (pKi (cpCasp2) = 7.75) with ≥525-fold selectivity over Casp1/3/4/5/6/7/9/10 and 24-fold over Casp8. MUR-2425 prevents the formation of neurotoxic Δtau314 in vitro, exhibits stable ADMET properties across human, rat, and mouse species and proves brain penetrance after subcutaneous injection in CD-1 mice. MUR-2425 is confirmed to engage Casp2 covalently by cocrystallization, supporting its further development for Alzheimer’s disease and related dementias.