2. Academic Validation
  3. Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers

Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers

  • J Am Chem Soc. 2024 Jul 10;146(27):18241-18252. doi: 10.1021/jacs.3c06483.
Eric D Huseman 1,  Anna Lo 1,  Olga Fedorova 2 3,  James L Elia 4,  Susan E Gueble 5,  Kingson Lin 1 4 5,  Ranjini K Sundaram 5,  Joonseok Oh 1 6,  Jinchan Liu 1,  Fabian Menges 1 7,  Matthew G Rees 8,  Melissa M Ronan 8,  Jennifer A Roth 8,  Victor S Batista 1,  Jason M Crawford 1 7 9,  Anna M Pyle 1 2 3,  Ranjit S Bindra 4 5,  Seth B Herzon 1 5 10
Affiliations

Affiliations

  • 1 Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.
  • 2 Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520, United States.
  • 3 Howard Hughes Medical Institute, New Haven, Connecticut 06520, United States.
  • 4 Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, United States.
  • 5 Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut 06520, United States.
  • 6 Institute of Biomolecular Design & Discovery, Yale University, West Haven, Connecticut 06516, United States.
  • 7 Department of Chemistry, Chemical and Biophysical Instrumentation Center, Yale University, New Haven, Connecticut 06520, United States.
  • 8 Broad Institute of MIT and Harvard; Cambridge, Massachusetts 02142, United States.
  • 9 Department of Microbial Pathogenesis, Yale School of Medicine; New Haven, Connecticut 06520, United States.
  • 10 Department of Pharmacology, Yale School of Medicine; New Haven, Connecticut 06520, United States.
PMID: 38815248 DOI: 10.1021/jacs.3c06483
Abstract

Aberrant DNA repair is a hallmark of Cancer, and many tumors display reduced DNA repair capacities that sensitize them to genotoxins. Here, we demonstrate that the differential DNA repair capacities of healthy and transformed tissue may be exploited to obtain highly selective chemotherapies. We show that the novel N3-(2-fluoroethyl)imidazotetrazine "KL-50" is a selective toxin toward tumors that lack the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT), which reverses the formation of O6-alkylguanine lesions. We establish that KL-50 generates DNA interstrand cross-links (ICLs) by a multistep process comprising DNA alkylation to generate an O6-(2-fluoroethyl)guanine (O6FEtG) lesion, slow unimolecular displacement of fluoride to form an N1,O6-ethanoguanine (N1,O6EtG) intermediate, and ring-opening by the adjacent cytidine. The slow rate of N1,O6EtG formation allows healthy cells expressing MGMT to reverse the initial O6FEtG lesion before it evolves to N1,O6EtG, thereby suppressing the formation of toxic DNA-MGMT cross-links and reducing the amount of DNA ICLs generated in healthy cells. In contrast, O6-(2-chloroethyl)guanine lesions produced by agents such as lomustine and the N3-(2-chloroethyl)imidazotetrazine mitozolomide rapidly evolve to N1,O6EtG, resulting in the formation of DNA-MGMT cross-links and DNA ICLs in healthy tissue. These studies suggest that careful consideration of the rates of chemical DNA modification and biochemical DNA repair may lead to the identification of Other tumor-specific genotoxic agents.

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