Being the first or second most common cause of premature death in over 100 countries, cancer imposes a major burden on modern societies worldwide. Inhibition of the Hedgehog pathway has had success, both in vitro and in the clinic, but resistance is a commonly encountered problem, making alternative Hedgehog modulators in high demand. Hhat is a membrane associated O-acyl transferase (MBOAT) whose only known function is the palmitoylation of Hedgehog, a posttranslational modification crucial for Hedgehog signalling. Targeting Hhat thus represents a uniquely specific way to target the hedgehog pathway that could be less prone to gaining resistance, but research in this area is hampered by a lack of good tool compounds. Here I propose to use cutting edge chemical biology tools to develop selective high potency Hhat inhibitors with thoroughly validated cellular activity. Such inhibitors are crucially needed to validate Hhat as a target in cancer therapy and the methodologies developed could be transferred to target other clinically relevant MBOATs in for example the Wnt pathway.
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