Chemical Biology in Antibiotic and Anticancer Drug Discovery

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• Thomas Lanyon-Hogg
• Monday 20 February 2023, 18:00-19:30
• Wolfson Lecture Theatre, Department of Chemistry, Lensfield Road.

If you have a question about this talk, please contact Daniel Lim.

Modern methods in chemical biology have accelerated various aspects of drug discovery, and this talk will describe the use of these interdisciplinary techniques in the development of molecules to combat cancer and antibiotic resistance. Hedgehog signalling regulates growth and is reactivated in certain cancers. The membrane protein Hedgehog acyltransferase (HHAT) is critical for signalling, making it an attractive therapeutic target. Only one HHAT inhibitor series existed in the literature, and in order to identify selective on-target inhibitors, compounds were analysed in silico, in cellular signalling assays, and via chemical proteomics. Photocrosslinking probes based on the best performing compound were developed to map the HHAT -inhibitor binding site, which provided new insights into HHAT ’s structure. Inhibitor development resulted in highly potent compound IMP -1575; however, intrinsic metabolic instability necessitated identification of new chemical series for continued clinical progression. Novel high-throughput HHAT assays were therefore developed, and a screening campaign resulted in successful identification of the most potent inhibitors to-date. Despite being a highly-challenging integral membrane protein, chemical biology has made HHAT a tractable target for drug discovery. The global emergence of antibiotic resistance is one of the most serious threats facing modern medicine, and there is an urgent need for new drug targets and small molecules with novel mechanisms of action. Inhibiting bacterial DNA repair by the AddAB complex can sensitize bacteria to DNA damage from the host immune system or antibiotics, and also block the ‘SOS response’ that drives mutation and resistance in bacteria. Rational, hypothesis-driven medicinal chemistry identified OXF -077 as a nanomolar potency compound that sensitizes methicillin-resistant S. aureus (MRSA) clinical isolates to fluoroquinolone antibiotics where resistance exists, and also inhibits the ‘SOS response’. In order to overcome bottlenecks in biological testing, high-throughput automated assays were established for compound analysis, and machine learning applied to accelerate optimisation of biochemical assays. Bacterial DNA repair therefore represents a novel therapeutic target and OXF -077 is a valuable tool molecule for development to combat the pressing global challenge of antibiotic resistance.

This talk is part of the SciSoc – Cambridge University Scientific Society series.

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