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

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

doi:10.1021/acs.jmedchem.0c01246

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. Epub 2020 Nov 20.

Authors

Jean Quancard¹, Oliver Simic¹, Carole Pissot Soldermann¹, Reiner Aichholz¹, Markus Blatter¹, Martin Renatus¹, Paulus Erbel¹, Samu Melkko¹, Ralf Endres¹, Mickael Sorge¹, Laurence Kieffer¹, Trixie Wagner¹, Karen Beltz¹, Paul Mcsheehy¹, Markus Wartmann¹, Catherine H Régnier¹, Thomas Calzascia¹, Thomas Radimerski¹, Marc Bigaud¹, Andreas Weiss¹, Frédéric Bornancin¹, Achim Schlapbach¹

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use
Blood / metabolism*
Caspase Inhibitors / chemical synthesis
Caspase Inhibitors / metabolism
Caspase Inhibitors / pharmacokinetics
Caspase Inhibitors / therapeutic use*
Cell Line, Tumor
Female
Half-Life
Humans
Mice, Inbred BALB C
Mice, SCID
Microsomes, Liver / metabolism
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / antagonists & inhibitors*
Neoplasms / drug therapy
Pyrazoles / chemical synthesis
Pyrazoles / metabolism
Pyrazoles / pharmacokinetics
Pyrazoles / therapeutic use*
Pyrimidines / chemical synthesis
Pyrimidines / metabolism
Pyrimidines / pharmacokinetics
Pyrimidines / therapeutic use*
Rats, Sprague-Dawley
Sheep
Urea / chemical synthesis
Urea / metabolism
Urea / pharmacokinetics
Urea / therapeutic use*
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Caspase Inhibitors
Pyrazoles
Pyrimidines
Urea
MALT1 protein, human
Malt1 protein, mouse
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein