Design, Synthesis, and Structure–Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors

Abstract

ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compounds, 6p binds tightly to ZAK protein (K d = 8.0 nM) and potently suppresses the kinase function of ZAK with singledigit nM (IC 50 = 4.0 nM) and exhibits excellent selectivity in a KINOMEscan screening platform against a panel of 403 wildtype kinases. This compound dose dependently blocks p38/GATA-4 and JNK/c-Jun signaling and demonstrates promising in vivo anti-HCM efficacy upon oral administration in a spontaneous hypertensive rat (SHR) model. Compound 6p may serve as a lead compound for new anti-HCM drug discovery.

P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection

“…2 M ). We also tested compound 6p (ZAKi), an inhibitor of the upstream MAP3K ZAKα ( Yang et al, 2020 ). Inflammasome assembly and IL-1β secretion were completely blocked by both p38 inhibitors as well as by ZAKi.…”

“…The following small compound inhibitors and reagents were used: 2-Deoxy-D-glucose (Sigma-Aldrich), anisomycin (Sigma-Aldrich), bafilomycin A1 (Sigma-Aldrich), berzosertib (Selleckchem), bestatin methyl ester (Abcam), blasticidin (InvivoGen), bortezomib (Selleckchem), cycloheximide (Sigma-Aldrich), deoxyribonucleic acid sodium salt from herring testes (Sigma-Aldrich), doramapimod (Cayman), doxycycline (Thermo Fisher Scientific), doxorubicin (Selleckchem), etoposide (Calbiochem), H 2 O 2 (Roth), ISRIB (Selleckchem), JNK-IN-8 (Selleckchem), KU-60019 (Selleckchem), lactimidomycin (Sigma-Aldrich), LPS-EK Ultrapure (Invivogen), MG-132 (Selleckchem), MLN4924 (MedChem Express), MLN7243 (ChemieTek), Nigericin sodium salt (Biomol), PF-3644022 (Sigma-Aldrich), SB202190 (Sigma-Aldrich), poly(dA:dT) (Invivogen), poly(I:C) low molecular weight and high molecular weight (Invivogen), sodium azide (Sigma-Aldrich), talabostat mesylate (MedChemExpress), Vx-765 (Selleckchem), and Z-VAD(Ome)-FMK (MedChemExpress). ZAKα inhibitor 6p ( Yang et al, 2020 ) was kindly provided by IFM Therapeutics. 6p was synthesized and characterized by 1 H NMR spectroscopy and LC-MS, with the data being fully consistent with literature values for this compound.…”

Collateral cleavage of 28s rRNA by RfxCas13d causes death of mice

“…We speculated that ZAKα may sense 28s rRNA breakage caused by RfxCas13d and activate JNK and p38 pathways. To test this, we firstly used two ZAK inhibitors (6p [33] and HY180) to block IEGs expression. IEGs expression can be inhibited by both inhibitors in a dose-dependent manner (Fig.…”

Glycyrrhiza uralensis root extract ameliorates high glucose‐induced renal proximal tubular fibrosis by attenuating tubular epithelial‐myofibroblast transdifferentiation by targeting TGF‐β1/Smad/Stat3 pathway

“…The transferred proteins on membranes were blocked using 5% nonfat milk for 1 hr at room temperature. The membranes were incubated with diluted primary antibodies (1:1000) overnight at 4°C (Chang et al., 2019; J. Yang et al., 2020). After five washes with Tris buffered saline containing 0.1% Tween‐20 the membrane was incubated with secondary antibodies for 1 hr at 37°C.…”