Optimization of the In Vivo Potency of Pyrazolopyrimidine MALT1 Protease Inhibitors by Reducing Metabolism and Increasing Potency in Whole Blood PMID: 33216547

ADC Targets in Oncology

2026-04-10

Optimization of the In Vivo Potency of Pyrazolopyrimidine MALT1 Protease Inhibitors by Reducing Metabolism and Increasing Potency in Whole Blood

J Med Chem. 2020 Dec 10;63(23):14594-14608. doi: 10.1021/acs.jmedchem.0c01246.

Jean Quancard ¹ , Oliver Simic ¹ , Carole Pissot Soldermann ¹ , Reiner Aichholz ¹ , Markus Blatter ¹ , Martin Renatus ¹ , Paulus Erbel ¹ , Samu Melkko ¹ , Ralf Endres ¹ , Mickael Sorge ¹ , Laurence Kieffer ¹ , Trixie Wagner ¹ , Karen Beltz ¹ , Paul Mcsheehy ¹ , Markus Wartmann ¹ , Catherine H Régnier ¹ , Thomas Calzascia ¹ , Thomas Radimerski ¹ , Marc Bigaud ¹ , Andreas Weiss ¹ , Frédéric Bornancin ¹ , Achim Schlapbach ¹

Affiliations

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.