Delving into the Latest Updates on XY-1-127 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

RIPK3

Action

modulators

Mechanism

RIPK3 modulators(receptor interacting serine/threonine kinase 3 modulators)

Therapeutic Areas

NeoplasmsDigestive System Disorders

Active Indication

Colorectal Cancer

Inactive Indication-

Originator Organization

Ningxia Medical University

Active Organization

Fudan University

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Necroptosis is confirmed as a precisely programmed cell death that is activated in caspase-deficient conditions. Receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like pseudokinase (MLKL) are the key regulators involved in the signaling pathway. However, accumulating evidence suggests that RIPK1 also works in apoptosis and inflammation pathways independent of necroptosis. Differently, RIPK3 signals necroptosis independent of RIPK1. Thus, identification of specific RIPK3 inhibitors is of great importance for the drug development associated with necroptosis. The benzothiazole carboxamide is a privileged scaffold as RIPK3 inhibitors developed by our group recently. In this study, we work on the phenyl group in-between of benzothiazole and carboxamide to profile the chemical space. Finally, a chlorinated derivative XY-1-127 was found to specifically inhibit necroptosis rather than apoptosis with an EC₅₀ value of 676.8 nM and target RIPK3 with a K_d of 420 nM rather than RIPK1 (K_d = 4300 nM). It was also confirmed to block the formation of necrosome by inhibiting RIPK3 phosphorylation at 1 μM in necroptosis cells. This work discovers the chemical space insights on the phenyl group of the substituted benzothiazole RIPK3 inhibitors and provides a new lead compound for further development.

100 Deals associated with XY-1-127

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