Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers
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...
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| Published in | Journal of the American Chemical Society Vol. 146; no. 27; pp. 18241 - 18252 |
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| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Chemical Society
10.07.2024
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| Subjects | |
| Online Access | Get full text |
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| 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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| AbstractList | 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. 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 O 6 -methylguanine-DNA-methyltransferase (MGMT), which reverses the formation of O 6 -alkylguanine lesions. We establish that KL-50 generates DNA interstrand cross-links (ICLs) by a multistep process comprising DNA alkylation to generate an O 6 -(2-fluoroethyl)guanine (O 6 FEtG) lesion, slow unimolecular displacement of fluoride to form an N1,O 6 -ethanoguanine (N1,O 6 EtG) intermediate, and ring-opening by the adjacent cytidine. The slow rate of N1,O 6 EtG formation allows healthy cells expressing MGMT to reverse the initial O 6 FEtG lesion before it evolves to N1,O 6 EtG, thereby suppressing the formation of toxic DNA–MGMT cross-links and reducing the amount of DNA ICLs generated in healthy cells. In contrast, O 6 -(2-chloroethyl)guanine lesions produced by agents such as lomustine and the N3-(2-chloroethyl)imidazotetrazine mitozolomide rapidly evolve to N1,O 6 EtG, 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. 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.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. 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. 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 O -methylguanine-DNA-methyltransferase (MGMT), which reverses the formation of O -alkylguanine lesions. We establish that KL-50 generates DNA interstrand cross-links (ICLs) by a multistep process comprising DNA alkylation to generate an O -(2-fluoroethyl)guanine (O FEtG) lesion, slow unimolecular displacement of fluoride to form an N1,O -ethanoguanine (N1,O EtG) intermediate, and ring-opening by the adjacent cytidine. The slow rate of N1,O EtG formation allows healthy cells expressing MGMT to reverse the initial O FEtG lesion before it evolves to N1,O EtG, thereby suppressing the formation of toxic DNA-MGMT cross-links and reducing the amount of DNA ICLs generated in healthy cells. In contrast, O -(2-chloroethyl)guanine lesions produced by agents such as lomustine and the N3-(2-chloroethyl)imidazotetrazine mitozolomide rapidly evolve to N1,O EtG, 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. |
| Author | Ronan, Melissa M. Pyle, Anna M. Gueble, Susan E. Herzon, Seth B. Roth, Jennifer A. Elia, James L. Menges, Fabian Liu, Jinchan Sundaram, Ranjini K. Lo, Anna Rees, Matthew G. Batista, Victor S. Lin, Kingson Fedorova, Olga Crawford, Jason M. Huseman, Eric D. Bindra, Ranjit S. Oh, Joonseok |
| AuthorAffiliation | Department of Chemistry Department of Pharmacology Department of Therapeutic Radiology Department of Pathology Department of Microbial Pathogenesis Department of Molecular, Cellular, and Developmental Biology Broad Institute of MIT and Harvard Institute of Biomolecular Design & Discovery Department of Chemistry, Chemical and Biophysical Instrumentation Center |
| AuthorAffiliation_xml | – name: Department of Molecular, Cellular, and Developmental Biology – name: Department of Pathology – name: Broad Institute of MIT and Harvard – name: Department of Microbial Pathogenesis – name: Department of Pharmacology – name: Department of Chemistry – name: Department of Therapeutic Radiology – name: Department of Chemistry, Chemical and Biophysical Instrumentation Center – name: Institute of Biomolecular Design & Discovery |
| Author_xml | – sequence: 1 givenname: Eric D. orcidid: 0000-0002-7550-1593 surname: Huseman fullname: Huseman, Eric D. organization: Department of Chemistry – sequence: 2 givenname: Anna orcidid: 0000-0002-4489-3109 surname: Lo fullname: Lo, Anna organization: Department of Chemistry – sequence: 3 givenname: Olga surname: Fedorova fullname: Fedorova, Olga organization: Department of Molecular, Cellular, and Developmental Biology – sequence: 4 givenname: James L. orcidid: 0000-0003-3962-7452 surname: Elia fullname: Elia, James L. organization: Department of Pathology – sequence: 5 givenname: Susan E. surname: Gueble fullname: Gueble, Susan E. organization: Department of Therapeutic Radiology – sequence: 6 givenname: Kingson orcidid: 0000-0002-5460-4008 surname: Lin fullname: Lin, Kingson organization: Department of Therapeutic Radiology – sequence: 7 givenname: Ranjini K. surname: Sundaram fullname: Sundaram, Ranjini K. organization: Department of Therapeutic Radiology – sequence: 8 givenname: Joonseok orcidid: 0000-0002-7616-1949 surname: Oh fullname: Oh, Joonseok organization: Institute of Biomolecular Design & Discovery – sequence: 9 givenname: Jinchan orcidid: 0000-0003-2217-1233 surname: Liu fullname: Liu, Jinchan organization: Department of Chemistry – sequence: 10 givenname: Fabian orcidid: 0000-0002-5859-9197 surname: Menges fullname: Menges, Fabian organization: Department of Chemistry, Chemical and Biophysical Instrumentation Center – sequence: 11 givenname: Matthew G. surname: Rees fullname: Rees, Matthew G. organization: Broad Institute of MIT and Harvard – sequence: 12 givenname: Melissa M. surname: Ronan fullname: Ronan, Melissa M. organization: Broad Institute of MIT and Harvard – sequence: 13 givenname: Jennifer A. surname: Roth fullname: Roth, Jennifer A. organization: Broad Institute of MIT and Harvard – sequence: 14 givenname: Victor S. orcidid: 0000-0002-3262-1237 surname: Batista fullname: Batista, Victor S. organization: Department of Chemistry – sequence: 15 givenname: Jason M. orcidid: 0000-0002-7583-1242 surname: Crawford fullname: Crawford, Jason M. organization: Department of Microbial Pathogenesis – sequence: 16 givenname: Anna M. orcidid: 0000-0001-9045-8872 surname: Pyle fullname: Pyle, Anna M. organization: Department of Molecular, Cellular, and Developmental Biology – sequence: 17 givenname: Ranjit S. surname: Bindra fullname: Bindra, Ranjit S. email: ranjit.bindra@yale.edu organization: Department of Therapeutic Radiology – sequence: 18 givenname: Seth B. orcidid: 0000-0001-5940-9853 surname: Herzon fullname: Herzon, Seth B. email: seth.herzon@yale.edu organization: Department of Pharmacology |
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| Snippet | 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... |
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| SubjectTerms | alkylation Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use brain Brain Neoplasms - drug therapy Brain Neoplasms - pathology Cell Line, Tumor crosslinking cytidine DNA DNA repair DNA Repair - drug effects drug resistance Drug Resistance, Neoplasm - drug effects fluorides Humans Imidazoles - chemistry Imidazoles - pharmacology Imidazoles - therapeutic use mechanism of action mutagens O-Methylguanine-DNA Methyltransferase - antagonists & inhibitors O-Methylguanine-DNA Methyltransferase - metabolism toxicity toxins |
| Title | Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers |
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