Delving into the Latest Updates on WX-02-23 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

PHF5A x SF3B1

Mechanism

PHF5A modulators(PHD finger protein 5A modulators), SF3B1 inhibitors(Splicing factor 3B subunit 1 inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Hematologic Neoplasms

Inactive Indication-

Originator Organization

The Rockefeller University

Active Organization

The Rockefeller University

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC26H25N3O5

InChIKeyYCIHYSVUQSOVJT-NLFFAJNJSA-N

CAS Registry2929223-36-7

The spliceosome protein, SF3B1 associates with U2 snRNP during early spliceosome assembly for pre-mRNA splicing. Frequent somatic mutations in SF3B1 observed in cancer necessitates characterization of its role in identifying the branchpoint adenosine of introns. Remarkably, SF3B1 is the target of three distinct natural product drugs, each identified by their potent anti-tumor properties. Structural studies indicate that SF3B1 conformational flexibility is functionally important, and also suggest that drug binding blocks the transition to a closed state of SF3B1 required for the next stage of spliceosome assembly. This model is confounded, however, by the antagonistic property of an inactive herboxidiene analog. In this study, we established an assay for the evaluating the thermostability of SF3B1 present in the nuclear extract preparations employed for in vitro splicing studies, with the aim of investigating inhibitor interactions with SF3B1 in a functional context. We show that both active and antagonistic analogs of natural product inhibitors affect SF3B1 thermostability, consistent with binding alone being insufficient to impair SF3B1 function. Surprisingly, SF3B1 thermostability differs among nuclear extract preparations, likely reflecting its conformational status. We also investigated a synthetic SF3B1 ligand, WX-02-23, and find that it increases SF3B1 thermostability and interferes with in vitro splicing by a mechanism that strongly resembles the activity of natural product inhibitors. We propose that altered SF3B1 thermostability can serve as an indicator of inhibitor binding to complement functional assays of their general effect on splicing. It may also provide a means to investigate the factors that influence SF3B1 conformation.

100 Deals associated with WX-02-23

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