The tightly regulated hedgehog (Hh) signalling pathway plays vital roles in embryonic development and tissue homeostasis, but uncontrolled activation is associated with certain cancers, including medulloblastoma and basal cell carcinoma (BCC). Although Hh pathway inhibitors have gained approval, they all target the seven-transmembrane region of the GPCR smoothened (SMO) — the central transducer of Hh signalling — and many tumours eventually acquire drug-resistant SMO mutations.
Liu et al. set out to identify novel Hh pathway inhibitors that act by blocking SMO cholesterylation, a process required for SMO activation. Screening a sterol library of 300 cholesterol analogues identified the tricyclic diterpenoid compound Q29 as a potent inhibitor of Hh pathway activity. In vitro studies confirmed SMO to be the target of Q29; the compound bound to the SMO cysteine rich domain to block cholesterylation.
Q29 inhibited proliferation of medulloblastoma cells in vitro. When administered by oral gavage to a mouse model of medulloblastoma, Q29 inhibited tumour growth and exhibited a synergistic inhibitory effect with vismodegib (a clinically used SMO inhibitor for treating BCC), without signs of toxicity or weight reduction. In vitro, Q29 inhibited cholesterylation of oncogenic SMO variants, as well as SMO mutants resistant to current SMO inhibitors.
