Delving into the Latest Updates on GNE-371 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

TAF1

Mechanism

TAF1 inhibitors(TATA-box binding protein associated factor 1 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

Genentech, Inc.

Active Organization

Genentech, Inc.

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC24H25N5O3

InChIKeyXJRUWGFZGQNPPD-UHFFFAOYSA-N

CAS Registry1926986-36-8

Author: Duplessis, Martin ; Cote, Alexandre ; Wang, Jian ; Crawford, Terry D. ; Jiang, Ying ; Magnuson, Steven R. ; Romero, F. Anthony ; Bellon, Steve ; Hewitt, Michael C. ; Cochran, Andrea G. ; Burdick, Daniel J. ; Taylor, Alexander M. ; Flynn, E. Megan ; Nasveschuk, Christopher G. ; Wang, Shumei ; Pardo, Eneida ; Zhu, Xiaoyu ; Jayaram, Hariharan ; Zawadzke, Laura E. ; Xu, Zhaowu ; Huang, Hon-Ren ; Tang, Yong ; Poy, Florence ; Cummings, Richard ; Beresini, Maureen H. ; Audia, James E. ; Joshi, Shivangi ; Tsui, Vickie ; Murray, Jeremy ; Albrecht, Brian K.

The biological functions of the dual bromodomains of human transcription-initiation-factor TFIID subunit 1 (TAF1(1,2)) remain unknown, although TAF1 has been identified as a potential target for oncology research. Here, we describe the discovery of a potent and selective in vitro tool compound for TAF1(2), starting from a previously reported lead. A cocrystal structure of lead compound 2 bound to TAF1(2) enabled structure-based design and structure-activity-relationship studies that ultimately led to our in vitro tool compound, 27 (GNE-371). Compound 27 binds TAF1(2) with an IC₅₀ of 10 nM while maintaining excellent selectivity over other bromodomain-family members. Compound 27 is also active in a cellular-TAF1(2) target-engagement assay (IC₅₀ = 38 nM) and exhibits antiproliferative synergy with the BET inhibitor JQ1, suggesting engagement of endogenous TAF1 by 27 and further supporting the use of 27 in mechanistic and target-validation studies.

100 Deals associated with GNE-371

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