Design, Synthesis, and Evaluation of Inhibitors of Hedgehog Acyltransferase

J Med Chem. 2024 Jan 25;67(2):1061-1078. doi: 10.1021/acs.jmedchem.3c01363.

Markus Ritzefeld ¹, Leran Zhang ¹, Zhangping Xiao ¹, Sebastian A Andrei ¹, Olivia Boyd ¹, Naoko Masumoto ¹, Ursula R Rodgers ², Markus Artelsmair ¹, Lea Sefer ³, Angela Hayes ⁴, Efthymios-Spyridon Gavriil ¹, Florence I Raynaud ⁴, Rosemary Burke ⁴, Julian Blagg ⁴, Henry S Rzepa ¹, Christian Siebold ³, Anthony I Magee ², Thomas Lanyon-Hogg ¹, Edward W Tate ¹

Affiliations

1 Department of Chemistry, Imperial College London, London W12 0BZ, U.K.
2 National Heart and Lung Institute, Imperial College London, London SW7 2AZ, U.K.
3 Division of Structural Biology, University of Oxford, Oxford OX3 7BN, U.K.
4 Division of Cancer Therapeutics, Centre for Cancer Drug Discovery, Institute of Cancer Research, London SM2 5NG, U.K.

PMID: 38198226 DOI: 10.1021/acs.jmedchem.3c01363

Abstract

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.

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