Imperial College London
Professor Henry S. Rzepa

Professor Henry S. Rzepa

Faculty of Natural Sciences, Department of Chemistry

Emeritus Professor of Computational Chemistry
 
 
 
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Contact

 

+44 (0)7514 623 653h.rzepa Website

 
 
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Location

 

501AMolecular Sciences Research HubWhite City Campus

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Summary

 

Publications

Citation

BibTex format

@article{Ritzefeld:2024:10.1021/acs.jmedchem.3c01363,
author = {Ritzefeld, M and Zhang, L and Xiao, Z and Andrei, S and Gavriil, E and Siebold, C and Lanyon-Hogg, T and Tate, E},
doi = {10.1021/acs.jmedchem.3c01363},
journal = {Journal of Medicinal Chemistry},
pages = {1061--1078},
title = {Design, synthesis and evaluation of inhibitors of hedgehog acyltransferase},
url = {http://dx.doi.org/10.1021/acs.jmedchem.3c01363},
volume = {67},
year = {2024}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Ritzefeld,M
AU  - Zhang,L
AU  - Xiao,Z
AU  - Andrei,S
AU  - Gavriil,E
AU  - Siebold,C
AU  - Lanyon-Hogg,T
AU  - Tate,E
DO  - 10.1021/acs.jmedchem.3c01363
EP  - 1078
PY  - 2024///
SN  - 0022-2623
SP  - 1061
TI  - Design, synthesis and evaluation of inhibitors of hedgehog acyltransferase
T2  - Journal of Medicinal Chemistry
UR  - http://dx.doi.org/10.1021/acs.jmedchem.3c01363
UR  - http://hdl.handle.net/10044/1/108910
VL  - 67
ER  -
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