Delving into the Latest Updates on MS-479 with Synapse

Overview

Basic Info

Drug Type

Proteolysis-targeting chimeras (PROTAC)

Synonyms

Target

SPOP

Action

inhibitors

Mechanism

SPOP inhibitors(speckle type BTB/POZ protein inhibitors)

Therapeutic Areas

NeoplasmsDigestive System Disorders

Active Indication

Colorectal Cancer

Inactive Indication-

Originator Organization

Icahn School of Medicine at Mount Sinai

Active Organization

Icahn School of Medicine at Mount Sinai

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Proteolysis Targeting Chimeras (PROTACs) represent promising therapeutic modalities for degrading disease-causing proteins. However, the development of effective PROTACs has been limited by the availability of suitable E3 ligase ligands. In this study, we demonstrate for the first time that SPOP, an unexplored E3 ligase, can be recruited to degrade target proteins of interest. We developed a bridged PROTAC strategy and successfully discovered a proof-of-concept PROTAC degrader 9 (MS479), which recruits the E3 ligase SPOP by directly binding its substrate GLP as a bridge protein. This approach facilitates the polyubiquitination and subsequent degradation of BRD4/3/2 by the 26S proteasome. 9 effectively reduced the protein level of BRD4 short isoform in a time-, concentration-, GLP-, SPOP-, and ubiquitin-proteasome system (UPS)-dependent manner. Additionally, 9 effectively inhibited the proliferation of colorectal cancer (CRC) cells. Overall, our study expands the limited repertoire of the E3 ligases that can be harnessed for targeted protein degradation.

100 Deals associated with MS-479

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