Discovery of Potent, Highly Selective, and In Vivo Efficacious, Allosteric MALT1 Inhibitors by Iterative Scaffold Morphing.
Basic Information
ID: ALA4673331
Journal: J Med Chem
Title: Discovery of Potent, Highly Selective, and In Vivo Efficacious, Allosteric MALT1 Inhibitors by Iterative Scaffold Morphing.
Authors: Pissot Soldermann C,Simic O,Renatus M,Erbel P,Melkko S,Wartmann M,Bigaud M,Weiss A,McSheehy P,Endres R,Santos P,Blank J,Schuffenhauer A,Bold G,Buschmann N,Zoller T,Altmann E,Manley PW,Dix I,Buchdunger E,Scesa J,Quancard J,Schlapbach A,Bornancin F,Radimerski T,Régnier CH
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.
CiteXplore: 33252239
DOI: 10.1021/acs.jmedchem.0c01245
Patent ID: ┄