Design of Cholesterol Biosynthesis Inhibitors as Anticancer Agents

Primary Supervisor: Dr David Leaver
Co-supervisors: Dr Boris Budiono and Dr Ken Chinkwo
Location: Wagga Wagga
Keywords: cancer, cholesterol, enzymes
Study Availability: Available until December 2027
Research Group: Medical Sciences

Synopsis:
Much research over the last several decades has been focused on finding novel anticancer agents that inhibit cholesterol biosynthesis, however, there has been little to no success in this endeavor and the pharmaceutical industry is reluctant to pursue sterol biosynthesis inhibitor drug development. Over the last couple of years structural biology advances have enabled the crystal structures of post-squalene cholesterogenesis enzymes to be solved that can be used to design novel cholesterol biosynthesis inhibitors. This project will use a structure guided approach to discover new anticancer drugs that selectively inhibit cholesterol biosynthesis enzymes.

Crystal structures of enzymes in the post-squalene segment of cholesterogenesis A: Crystal structure of squalene monooxygenase bound with FAD (black) and “Cmpd 4” (blue), PDB 6C6N; B: Crystal structure of lanosterol synthase bound with lanosterol (black), PDB 1W6K; C: Crystal structure of Emopamil-Binding Protein bound with U18666A (red), PDB 6OHT; D: Crystal structure of sterol 14α-methyl demethylase bound with ketoconazole (red), PDB 3LD6. Figure adapted from Biochemical Pharmacology 2022, 196, 114611.

Interested? Start the conversation here by contacting Dr David Leaver

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