Design of chemical probes for hedgehog acyltransferase

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The Hedgehog (Hh) signalling pathway is a conserved paracrine pathway that plays a physiological role primarily in embryonic development. However, in adults upregulated Hh signalling is involved in an estimated 25% of all cancer deaths. Iinhibitors targeting downstream Hh signalling in the 'receiving' cells, are first line therapy in certain Hh-dependent cancers. Although initially highly effective, most patients progress within one year due to resistance indicating the pressing need for new approaches which could be used in combination. Hedgehog acyltransferase (HHAT) is required for generation of the Hh signal through palmitoylation of Hh protein in the 'producing' cell. We have discovered multiple novel, validated and chemically diverse HHAT inhibitor hit series, with outstanding potency (100nM and below) in vitro, up to 50-fold more potent than any previously reported, with varied and developable properties. We have further established synthetic routes and analogues of improved potency, the first cryo-EM structures of HHAT bound to each class of inhibitor, and a full suite of biochemical and cellular assays for HHAT inhibition. Supported by a team of scientists in drug discovery, structural biology and pharmacokinetic analysis, this project will contribute to discovery of the first highly potent and selective HHAT inhibitors as chemical biology tools to validate HHAT as a novel target in preclinical translational cancer models.