Delving into the Latest Updates on IMP-1575 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

HHAT

Mechanism

HHAT inhibitors(Cysteine N-palmitoyltransferase HHAT inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

Imperial College London

Active Organization

Imperial College London

Inactive Organization-

Drug Highest PhaseDiscovery

First Approval Date-

Regulation-

Structure

Molecular FormulaC19H25N3OS

InChIKeyOVUGAMKQXDOHDJ-LJQANCHMSA-N

CAS Registry-

Author: Gavriil, Efthymios-Spyridon ; Raynaud, Florence I. ; Andrei, Sebastian A. ; Hayes, Angela ; Magee, Anthony I. ; Xiao, Zhangping ; Siebold, Christian ; Masumoto, Naoko ; Boyd, Olivia ; Rzepa, Henry S. ; Tate, Edward W. ; Ritzefeld, Markus ; Lanyon-Hogg, Thomas ; Zhang, Leran ; Artelsmair, Markus ; Blagg, Julian ; Sefer, Lea ; Burke, Rosemary ; Rodgers, Ursula R.

Hedgehog signaling is involved in embryonic development and cancer growth. Functional activity of secreted Hedgehog signaling proteins is dependent on N-terminal palmitoylation, making the palmitoyl transferase Hedgehog acyltransferase (HHAT), a potential drug target and a series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines have been identified as HHAT inhibitors. Based on structural data, we designed and synthesized 37 new analogues which we profiled alongside 13 previously reported analogues in enzymatic and cellular assays. Our results show that a central amide linkage, a secondary amine, and (R)-configuration at the 4-position of the core are three key factors for inhibitory potency. Several potent analogues with low- or sub-μM IC₅₀ against purified HHAT also inhibit Sonic Hedgehog (SHH) palmitoylation in cells and suppress the SHH signaling pathway. This work identifies IMP-1575 as the most potent cell-active chemical probe for HHAT function, alongside an inactive control enantiomer, providing tool compounds for validation of HHAT as a target in cellular assays.

100 Deals associated with IMP-1575

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