Optimization of the <i>In Vivo</i> Potency of Pyrazolopyrimidine MALT1 Protease Inhibitors by Reducing Metabolism and Increasing Potency in Whole Blood
Jean Quancard, Oliver Simić, Carole Pissot‐Soldermann, Reiner Aichholz, Markus Blatter, Martin Renatus, P. Erbel, Samu Melkko, Ralf Endres, Mickaël Sorge, Laurence Kieffer, Trixie Wagner, Karen Beltz, Paul M.J. McSheehy, Markus Wartmann, Catherine H. Régnier, Thomas Calzascia, Thomas Radimerski, Marc Bigaud, Andreas Weiss, Frédéric Bornancin, Achim Schlapbach
Abstract
The paracaspase MALT1 has gained increasing interest as a target for the treatment of subsets of lymphomas as well as autoimmune diseases, and there is a need for suitable compounds to explore the therapeutic potential of this target. Here, we report the optimization of the in vivo potency of pyrazolopyrimidines, a class of highly selective allosteric MALT1 inhibitors. High doses of the initial lead compound led to tumor stasis in an activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) xenograft model, but this compound suffered from a short in vivo half-life and suboptimal potency in whole blood. Guided by metabolism studies, we identified compounds with reduced metabolic clearance and increased in vivo half-life. In the second optimization step, masking one of the hydrogen-bond donors of the central urea moiety through an intramolecular interaction led to improved potency in whole blood. This was associated with improved in vivo potency in a mechanistic model of B cell activation. The optimized compound led to tumor regression in a CARD11 mutant ABC-DLBCL lymphoma xenograft model.