Delving into the Latest Updates on WS-383 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

DCN1 inhibitors(Defective cullin neddylation protein 1 inhibitors), UBE2M inhibitors(ubiquitin conjugating enzyme E2 M inhibitors)

Therapeutic Areas-

Active Indication-

Inactive Indication-

Originator Organization

Zhengzhou University

Active Organization

University of Michigan

Zhengzhou University

Inactive Organization-

Drug Highest PhaseDiscovery

First Approval Date-

Regulation-

Structure

Molecular FormulaC18H20ClN9S2

InChIKeyMGESDQAAIJOGJA-UHFFFAOYSA-N

CAS Registry2247543-65-1

The cullin-RING ubiquitin ligases (CRLs) are responsible for about 20% of cellular protein degradation and regulate diverse cellular processes, and the dysfunction of CRLs is implicated in human diseases. Targeting the CRLs has become an emerging strategy for the treatment of human diseases. Herein, we describe the discovery of a hit compound from our in-house library and further structure-based optimizations, which have enabled the identification of new triazolo[1,5- a]pyrimidine-based inhibitors targeting the DCN1-UBC12 interaction. Compound WS-383 blocks the DCN1-UBC12 interaction (IC₅₀ = 11 nM) reversibly and shows selectivity over selected kinases. WS-383 exhibits cellular target engagement to DCN1 in MGC-803 cells. WS-383 inhibits Cul3/1 neddylation selectively over other cullins and also induces accumulation of p21, p27, and NRF2. Collectively, targeting the DCN1-UBC12 interaction would be a viable strategy for selective neddylation inhibition of Cul3/1 and may be of therapeutic potential for disease treatment in which Cul3/1 is dysregulated.

100 Deals associated with WS-383

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