Delving into the Latest Updates on SZM-610 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

RIPK1 inhibitors(Receptor-interacting serine/threonine-protein kinase 1 inhibitors), RIPK3 inhibitors(receptor interacting serine/threonine kinase 3 inhibitors)

Therapeutic Areas

Other Diseases

Active Indication

Inflammation

Inactive Indication-

Originator Organization

Zhejiang University of Technology

Active Organization

Zhejiang University of Technology

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC26H19F4N3O4S

InChIKeyPZBUOCXBGCVSAF-UHFFFAOYSA-N

CAS Registry2304617-33-0

Necroptosis, a regulated cell death form, is a critical contributor in various inflammatory diseases. We previously identified a phenoxybenzothiazole SZM-610 as a RIPK1 and RIPK3 necroptosis inhibitor. We conducted extensive studies to investigate different chemical components' effects on antinecroptosis activity and RIPK1/3 activity. This study focused on replacing the linker in phenoxybenzothiazoles to assess its impact. Remarkably, compound 10, bearing a novel 3,2'-phenylbenzothiazole scaffold, exhibited fourfold more potent nanomolar activity than SZM-610. Unlike SZM-610, this compound inhibited RIPK1 (K_d = 17 nM) and eliminated RIPK3 inhibition at 5000 nM. Various linkages confirmed the 3,2'-phenylbenzothiazole superior potency. Moreover, this compound specifically inhibited necroptosis by inhibiting RIPK1, RIPK3, and MLKL phosphorylation. In a TNF-induced inflammatory model, it dose-dependently (1.25-5 mg/kg) protected mice from hypothermia and death, surpassing SZM-610's effectiveness. These findings highlight 3,2'-phenylbenzothiazole as a promising lead structure for developing drugs targeting necroptosis-related diseases.

100 Deals associated with SZM-610

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