Advancing a benzothiazole-derivative as a novel treatment for hepatocellular carcinoma
Dr. Joan Mayol Llinas (Post-doctoral Fellow)
[Supervisor: Professor Clive Chung]

Hepatocellular carcinoma (HCC) is a common liver cancer with limited treatment options and high mortality. AGPAT4, an acyltransferase protein involved in de novo lipid synthesis, has been identified as a driver of tumor plasticity in HCC, which is associated with drug resistance and tumor relapse. Therefore, AGPAT4 is a promising target for discovery of novel therapeutics against HCC. Activity-based protein profiling (ABPP) is a powerful chemoproteomic technique used in drug discovery to identify targetable sites on proteins. Using a competitive ABPP workflow, a benzothiazole compound CL26 has been identified as a selective and effective covalent inhibitor of AGPAT4. We have initiated a medicinal chemistry campaign to optimise the molecular structure of CL26. This approach involves a structure-based ligand design, in which CL26 analogues are being designed, synthesised and evaluated in order to improve covalent and non-covalent interactions with AGPAT4, as well as acquiring a desirable pharmacokinetic profile. The aim is to deliver a new lead candidate for pre-clinical evaluation.

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