BEGIN:VCALENDAR VERSION:2.0 PRODID:-//132.216.98.100//NONSGML kigkonsult.se iCalcreator 2.20.4// BEGIN:VEVENT UID:20250812T113703EDT-1997TKiNuC@132.216.98.100 DTSTAMP:20250812T153703Z DESCRIPTION:Abstract:\n\nEnzymes that repair DNA damage are expressed in he althy tissue but display reduced activity in many cancers. O6-Methylguanin e-DNA methyltransferase (MGMT) is one such enzyme that converts O6-alkylgu anosine to guanosine by nucleophilic displacement. MGMT is silenced in app roximately half of glioblastomas and 70% of lower-grade gliomas. Patients with MGMT-silenced glioblastoma typically receive surgery followed by radi ation therapy and the DNA alkylation agent temozolomide. Temozolomide gene rates O6-methylguanosine under physiological conditions and the drug’s mec hanism of action relies on an intact DNA-mismatch repair pathway. The trea tment provides just a ~7 mo. survival benefit since acquired resistance vi a silencing of the mismatch repair pathway is common. More than 95% of the se patients die within 5 years.\n\nHere I will describe the design\, synth esis\, and mechanism of action of the first MGMT-dependent\, mismatch repa ir-independent DNA alkylation agent\, a novel fluoroethyl imidazotetrazine (KL-50). KL-50 produces DNA interstrand cross-links specifically in MGMT- silenced cells. These interstrand cross-links form by initial production o f O6-(2-fluoroethyl)guanosine\, followed by a slow cyclization to an N1\,O 6-ethanoguanine intermediate\, and a similarly slow ring opening by the ad jacent thymidine base. The selectivity of KL-50 derives from the faster re lative rate of reversal of O6-(2-fluoroethyl)guanosine in healthy cells. K L-50 is efficacious and well-tolerated in animal models of temozolomide-re sistant glioblastoma. The structural similarity to temozolomide also provi des optimism that it may be translatable to the clinic. Integrating the re lative rates of chemical DNA modification and biochemical DNA repair into design of chemotherapies may provide opportunities for the treatment of ot her cancers harboring specific\, tumor-associated DNA repair defects\n\n  \n\nBio:\n\nSeth Herzon completed his undergraduate studies at Temple Univ ersity\, obtained a PhD in 2006 from Harvard University under the guidance of Professor Andrew G. Myers\, and was an NIH postdoctoral fellow with Pr ofessor John F. Hartwig at the University of Illinois\, Urbana–Champaign. He began at Yale in 2008 and is currently the Milton Harris ’29 Ph.D. Prof essor of Chemistry. He holds joint appointments in the Departments of Phar macology and Therapeutic Radiology at the Yale School of Medicine and is a Member of the Yale Cancer Center. Herzon's research is centered on organi c synthesis with an emphasis on the molecular mechanism of action and stru cture–function studies of anticancer and microbiome-derived secondary meta bolites. He is a co-founder of Modifi Biosciences\, which seeks to develop new therapeutics for the treatment of DNA repair deficient tumors. From 2 018–2023 has served as an Associate Editor for The Journal of Organic Chem istry.\n\nHe has been recognized for his accomplishments by a number of aw ards\, including an NSF CAREER Award\, a Searle Scholar Award\, a Fellowsh ip from the David and Lucile Packard Foundation\, a Fellowship from the Al fred P. Sloan Foundation\, a Cottrell Scholar Award of the Research Corpor ation for Scientific Advancement\, a Research Scholar Award from the Ameri can Cancer Society\, the Arthur C. Cope Scholar Award of the American Chem ical Society\, the Novartis Chemistry Lectureship\, the Synthesis/Synlett Award in Organic Chemistry\, the Elias J. Corey Award for Outstanding Orig inal Contribution in Organic Synthesis by a Young Investigator\, the Thiem e–IUPAC Award\, the Tetrahedron Young Investigator Award in Organic Synthe sis\, the Wilson Prize\, a Yale Faculty Innovation Award\, a Creativity Ex tension Award from the National Science Foundation\, and the ACS Award for Creative Work in Synthetic Organic Chemistry. From 2018–2019 he was a mem ber of the United States Defense Science Study Group\, Sponsored by the In stitute for Defense Analyses.\n DTSTART:20241029T170000Z DTEND:20241029T183000Z LOCATION:OM 10\, Maass Chemistry Building\, CA\, QC\, Montreal\, H3A 0B8\, 801 rue Sherbrooke Ouest SUMMARY:Chemical Society Seminar: Seth Herzon- Bad leaving groups make bett er strategy: KL-50\, DNA methyltransferases\, and drug-resistant glioblast oma. URL:/chemistry/channels/event/chemical-society-seminar -seth-herzon-bad-leaving-groups-make-better-strategy-kl-50-dna-358415 END:VEVENT END:VCALENDAR