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Abstract:

Enzymes that repair DNA damage are expressed in healthy tissue but display reduced activity in many cancers. O⁶-Methylguanine-DNA methyltransferase (MGMT) is one such enzyme that converts O⁶-alkylguanosine to guanosine by nucleophilic displacement. MGMT is silenced in approximately half of glioblastomas and 70% of lower-grade gliomas. Patients with MGMT-silenced glioblastoma typically receive surgery followed by radiation therapy and the DNA alkylation agent temozolomide. Temozolomide generates O⁶-methylguanosine under physiological conditions and the drug’s mechanism of action relies on an intact DNA-mismatch repair pathway. The treatment provides just a ~7 mo. survival benefit since acquired resistance via silencing of the mismatch repair pathway is common. More than 95% of these patients die within 5 years.

Here I will describe the design, synthesis, and mechanism of action of the first MGMT-dependent, mismatch repair-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 of O⁶-(2-fluoroethyl)guanosine, followed by a slow cyclization to an N¹,O⁶-ethanoguanine intermediate, and a similarly slow ring opening by the adjacent thymidine base. The selectivity of KL-50 derives from the faster relative rate of reversal of O⁶-(2-fluoroethyl)guanosine in healthy cells. KL-50 is efficacious and well-tolerated in animal models of temozolomide-resistant glioblastoma. The structural similarity to temozolomide also provides optimism that it may be translatable to the clinic. Integrating the relative rates of chemical DNA modification and biochemical DNA repair into design of chemotherapies may provide opportunities for the treatment of other cancers harboring specific, tumor-associated DNA repair defects

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Bio:

Seth Herzon completed his undergraduate studies at Temple University, obtained a PhD in 2006 from Harvard University under the guidance of Professor Andrew G. Myers, and was an NIH postdoctoral fellow with Professor 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. Professor of Chemistry. He holds joint appointments in the Departments of Pharmacology and Therapeutic Radiology at the Yale School of Medicine and is a Member of the Yale Cancer Center. Herzon's research is centered on organic synthesis with an emphasis on the molecular mechanism of action and structure–function studies of anticancer and microbiome-derived secondary metabolites. He is a co-founder of Modifi Biosciences, which seeks to develop new therapeutics for the treatment of DNA repair deficient tumors. From 2018–2023 has served as an Associate Editor for The Journal of Organic Chemistry.

He has been recognized for his accomplishments by a number of awards, including an NSF CAREER Award, a Searle Scholar Award, a Fellowship from the David and Lucile Packard Foundation, a Fellowship from the Alfred P. Sloan Foundation, a Cottrell Scholar Award of the Research Corporation for Scientific Advancement, a Research Scholar Award from the American Cancer Society, the Arthur C. Cope Scholar Award of the American Chemical Society, the Novartis Chemistry Lectureship, the Synthesis/Synlett Award in Organic Chemistry, the Elias J. Corey Award for Outstanding Original Contribution in Organic Synthesis by a Young Investigator, the Thieme–IUPAC Award, the Tetrahedron Young Investigator Award in Organic Synthesis, the Wilson Prize, a Yale Faculty Innovation Award, a Creativity Extension Award from the National Science Foundation, and the ACS Award for Creative Work in Synthetic Organic Chemistry. From 2018–2019 he was a member of the United States Defense Science Study Group, Sponsored by the Institute for Defense Analyses.