2. Academic Validation
  3. Discovery of Potent, Highly Selective, and In Vivo Efficacious, Allosteric MALT1 Inhibitors by Iterative Scaffold Morphing

Discovery of Potent, Highly Selective, and In Vivo Efficacious, Allosteric MALT1 Inhibitors by Iterative Scaffold Morphing

  • J Med Chem. 2020 Dec 10;63(23):14576-14593. doi: 10.1021/acs.jmedchem.0c01245.
Carole Pissot Soldermann 1,  Oliver Simic 1,  Martin Renatus 1,  Paulus Erbel 1,  Samu Melkko 1,  Markus Wartmann 1,  Marc Bigaud 1,  Andreas Weiss 1,  Paul McSheehy 2,  Ralf Endres,  Paulo Santos,  Jutta Blank 1,  Ansgar Schuffenhauer 1,  Guido Bold 1,  Nicole Buschmann 1,  Thomas Zoller 1,  Eva Altmann 1,  Paul W Manley 1,  Ina Dix 1,  Elisabeth Buchdunger 1,  Julien Scesa 1,  Jean Quancard 1,  Achim Schlapbach 1,  Frédéric Bornancin 1,  Thomas Radimerski 2,  Catherine H Régnier 1
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
  • 2 Basilea Pharmaceutica, CH-4002 Basel, Switzerland.
PMID: 33252239 DOI: 10.1021/acs.jmedchem.0c01245
Abstract

MALT1 plays a central role in immune cell activation by transducing NF-κB signaling, and its proteolytic activity represents a key node for therapeutic intervention. Two cycles of scaffold morphing of a high-throughput biochemical screening hit resulted in the discovery of MLT-231, which enabled the successful pharmacological validation of MALT1 allosteric inhibition in preclinical models of humoral immune responses and B-cell lymphomas. Herein, we report the structural activity relationships (SARs) and analysis of the physicochemical properties of a pyrazolopyrimidine-derived compound series. In human T-cells and B-cell lymphoma lines, MLT-231 potently and selectively inhibits the proteolytic activity of MALT1 in NF-κB-dependent assays. Both in vitro and in vivo profiling of MLT-231 support further optimization of this in vivo tool compound toward preclinical characterization.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-131902
    99.55%, MALT1 Inhibitor