Structure–activity relationship studies of 3-substituted pyrazoles as novel allosteric inhibitors of MALT1 protease

3D-QSAR, molecular docking and molecular dynamics analysis of pyrazole derivatives as MALT1 inhibitors

“…The structures and activities of 46 MALT1 inhibitors were collected from the literature 8,9 and optimized using sybyl.2.0 software. 10 The structure and related activity data are shown in Table S1 (ESI †).…”

“…A series of pyrazole-3-carboxamide derivatives reported by Ken Nunettsu Asaba et al 8,9 explored substituents at the 1-and 5-positions of pyrazole and the amide nitrogen at the 3-position of pyrazole, centred on pyrazole-3carboxamide, to discover a series of new MALT1 inhibitors. In order to obtain better MALT1 inhibitors, improve their efficacy and reduce drug resistance, we have systematically investigated the conformational relationships of these inhibitors on the basis of their activities and structures using 3D-QSAR, molecular docking and molecular dynamics simulation with certain structural modifications, and developed several novel MALT1 inhibitors with high activities.…”

Discovery and optimization of cyclohexane-1,4-diamines as allosteric MALT1 inhibitors

“…Removing the chloro substituent (9) leads to a >100-fold loss in potency, whereas replacing the chloro by a bromo (10) or a thiomethyl group (11) results in only slightly reduced potency. Alkyl residues like methyl (12), cyclopropyl (13), or trifluoromethyl (14) as well as an amino substituent (15) all result in a significant loss of potency, highlighting the importance of the nature of this substituent for MALT1 potency.…”

“…The potential role of MALT1 inhibition in B-cell lymphoma [5,6] and autoimmune disease has spurred the interest in MALT1 inhibitors as reported, among others [7], by Novartis [8e10], Janssen [11e13], Toray Industries [14], the Helmholtz Zentrum Munich and collab-orators [15], and a collaboration between Weill Cornell Medicine, Dana-Farber Cancer Institute, and Harvard Medical School [16]. Herein we describe our discovery and optimization of a novel series of allosteric MALT1 inhibitors with the most advanced compound showing single digit micromolar cell potency, excellent in vivo PK, and high selectivity in secondary pharmacology panels including 16 proteases.…”