ETS2400

The Hedgehog pathway plays a critical role during development, regulating patterning and proliferation. It is reactivated in many cancers.

Hedgehog Pathway inhibition: mitigating therapeutic resistance

Loss-of-function Patched mutations are associated with Gorlin and Li-Fraumeni syndromes and predispose individuals to basal cell carcinomas, medulloblastomas, and rhabdomyosarcomas. Activating mutations of SMO are also found in basal cell carcinomas and rare SUFU mutations in medulloblastomas, underscoring the involvement of the pathway in cancer.

The targeting of the pathway has been validated in cancer by the first generation of inhibitory molecules, which have targeted “SMO”. The most advanced of these agents, vismodegib and sonidegib, have been approved for use in the treatment of basal-cell carcinoma. Initial tumour responses are often impressive, but resistance is frequently observed. This has limited the clinical impact of these otherwise potentially important agents in cancer.

Our programme focuses on potent, selective Hedgehog pathway inhibitors with a reduced tendency to induce resistance, together with activity against tumours that are resistant to SMO inhibition. Mutation, amplification and deletion data indicate that the pathway as a whole is critical, and hence targeting a single component, such as SMO, will be a strong driver for mutation and clonal selection and the emergence of resistance. Targeting across several proteins that participate in the Hedgehog pathway reduces opportunity for the cancer cells to evolve around the drug’s action and so reduces the risk of target and pathway resistance.

A molecule showing potency in cellular assays in the nanomolar range, as potent as the leading SMO inhibitors, while not binding SMO, is shown below. Molecules in this family are well placed either to rescue SMO inhibitors from therapeutic resistance or displace them.

Hedgehog Figure

Our lead compounds are small molecules:

  • with potency in cellular assays in the nanomolar range, and as potent as the leading SMO inhibitors
  • while not binding SMO
  • well placed to rescue existing SMO inhibitors from therapeutic resistance, or displace them
  • have good variability in chemotypes
  • with synthetic tractability
  • have good drug-like characteristics.