A new class of drug compounds blocks the Hedgehog signalling pathway at its source, offering a potential treatment for the scarring diseases that underlie 45% of deaths in developed countries. The problem: Fibrotic diseases—where organs like the lungs, liver, kidneys, heart, or skin become stiff and scarred—have almost no effective treatments. Existing drugs that target the Hedgehog pathway, approved for some cancers, fail in fibrosis because they hit only one part of the pathway (the Smoothened protein), cause resistance, and disrupt other cellular processes. The researchers have developed inhibitors of a different target, Hedgehog Acyltransferase (HHAT), which modifies the signalling molecules themselves. Their compounds are over 100-fold more potent than previous HHAT inhibitors, are orally bioavailable, and show no detectable off-target toxicity. If these inhibitors succeed in preclinical fibrosis models, they could become first-in-class drugs for millions of patients with pulmonary, hepatic, renal, cardiac, or dermal fibrosis—conditions that currently have no cure. The approach is mechanistically distinct from existing therapies, blocking both Smoothened-dependent and independent signalling without affecting other pathways.
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The Hedgehog signalling pathway, with a well-established role in cancer, is also aberrantly activated in a range of fibrotic diseases, including pulmonary, hepatic, renal, cardiac and dermal fibrosis. In developed countries, 45% of deaths are linked to fibrosis, indicating its substantial socioeconomic burden. However, there remains a striking lack of effective therapeutic options for fibrotic diseases, highlighting the urgent need for new treatment strategies. Three Hedgehog pathway inhibitors have been approved for cancer treatment, and all act via the same target, the transmembrane protein Smoothened (SMO). However, their efficacy is limited to a small subset of Hedgehog-related diseases, due to resistance, SMO-independent Hedgehog signalling and because they impair the anti-tumour immune response. In addition, they suffer from low tolerability, which could be attributed to the fact that SMO interacts with other pathways in cells. Hedgehog Acyltransferase (HHAT), the focus of this project, catalyses the lipid modification required to activate the Hedgehog signalling ligands. HHAT has been previously identified as a target in several cancers. Importantly, it has recently emerged as an attractive target in fibrotic diseases, as genetic targeting of HHAT has demonstrated impressive therapeutic benefit in preclinical models of fibrosis. In contrast with SMO inhibitors, HHAT inhibitors block selectively Hedgehog signalling at its origin, stop both SMO-dependent and independent aspects of the pathway and do not affect other cellular processes. As a result, HHAT inhibition represents a mechanistically distinct and potentially superior therapeutic approach in cases where SMO-targeting drugs have shown limited success. Existing HHAT inhibitors suffer from poor metabolic stability and off-target effects. Funded previously by the MRC Impact Acceleration Award, we have developed novel HHAT inhibitors that are over 100-fold more potent than the reported molecules, with no detectable off-target toxicity and demonstrated oral bioavailability. In this project, we aim to evaluate the therapeutic potential of lead HHAT inhibitors in relevant fibrosis models, de-risking HHAT as a drug target and progressing towards clinical candidate nomination. Given the central role of Hedgehog signalling in cancer and fibrosis, the successful development of first-in-class HHAT inhibitors could deliver transformative new therapies for millions of patients worldwide.
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