2. Academic Validation
  3. Optimization of the In Vivo Potency of Pyrazolopyrimidine MALT1 Protease Inhibitors by Reducing Metabolism and Increasing Potency in Whole Blood

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

Affiliation

  • 1 Novartis Pharma AG, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
PMID: 33216547 DOI: 10.1021/acs.jmedchem.0c01246
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.

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