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SUMMARY:Chemical Biology in Antibiotic and Anticancer Drug Discovery - Tho
 mas Lanyon-Hogg
DTSTART:20230220T180000Z
DTEND:20230220T193000Z
UID:TALK197620@talks.cam.ac.uk
CONTACT:Daniel Lim
DESCRIPTION:Modern methods in chemical biology have accelerated various as
 pects of drug discovery\, and this talk will describe the use of these int
 erdisciplinary techniques in the development of molecules to combat cancer
  and antibiotic resistance.  Hedgehog signalling regulates growth and is r
 eactivated in certain cancers. The membrane protein Hedgehog acyltransfera
 se (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 analyse
 d in silico\, in cellular signalling assays\, and via chemical proteomics.
  Photocrosslinking probes based on the best performing compound were devel
 oped to map the HHAT-inhibitor binding site\, which provided new insights 
 into HHAT’s structure. Inhibitor development resulted in highly potent c
 ompound 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 screeni
 ng campaign resulted in successful identification of the most potent inhib
 itors to-date. Despite being a highly-challenging integral membrane protei
 n\, chemical biology has made HHAT a tractable target for drug discovery. 
 The global emergence of antibiotic resistance is one of the most serious t
 hreats facing modern medicine\, and there is an urgent need for new drug t
 argets and small molecules with novel mechanisms of action. Inhibiting bac
 terial DNA repair by the AddAB complex can sensitize bacteria to DNA damag
 e from the host immune system or antibiotics\, and also block the ‘SOS r
 esponse’ that drives mutation and resistance in bacteria. Rational\, hyp
 othesis-driven medicinal chemistry identified OXF-077 as a nanomolar poten
 cy compound that sensitizes methicillin-resistant S. aureus (MRSA) clinica
 l isolates to fluoroquinolone antibiotics where resistance exists\, and al
 so inhibits the ‘SOS response’. In order to overcome bottlenecks in bi
 ological testing\, high-throughput automated assays were established for c
 ompound 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. 
LOCATION:Wolfson Lecture Theatre\,  Department of Chemistry\, Lensfield Ro
 ad
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