Design, Synthesis, and Evaluation of Inhibitors of Hedgehog Acyltransferase.

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

SUBMITTER: Ritzefeld M 

PROVIDER: S-EPMC10823475 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature