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Isoquinoline thiosemicarbazone displays potent anticancer activity with in vivo efficacy against aggressive leukemias.
Sun, Daniel L; Poddar, Soumya; Pan, Roy D; Rosser, Ethan W; Abt, Evan R; Van Valkenburgh, Juno; Le, Thuc M; Lok, Vincent; Hernandez, Selena P; Song, Janet; Li, Joanna; Turlik, Aneta; Chen, Xiaohong; Cheng, Chi-An; Chen, Wei; Mona, Christine E; Stuparu, Andreea D; Vergnes, Laurent; Reue, Karen; Damoiseaux, Robert; Zink, Jeffrey I; Czernin, Johannes; Donahue, Timothy R; Houk, Kendall N; Jung, Michael E; Radu, Caius G.
Afiliação
  • Sun DL; Department of Molecular and Medical Pharmacology , University of California, Los Angeles , California 90095 , USA . Email: cradu@mednet.ucla.edu.
  • Poddar S; Ahmanson Translational Imaging Division , University of California, Los Angeles , California 90095 , USA.
  • Pan RD; Department of Chemistry and Biochemistry , University of California, Los Angeles , California 90095 , USA . Email: jung@chem.ucla.edu.
  • Rosser EW; Department of Molecular and Medical Pharmacology , University of California, Los Angeles , California 90095 , USA . Email: cradu@mednet.ucla.edu.
  • Abt ER; Ahmanson Translational Imaging Division , University of California, Los Angeles , California 90095 , USA.
  • Van Valkenburgh J; Department of Molecular and Medical Pharmacology , University of California, Los Angeles , California 90095 , USA . Email: cradu@mednet.ucla.edu.
  • Le TM; Ahmanson Translational Imaging Division , University of California, Los Angeles , California 90095 , USA.
  • Lok V; Department of Chemistry and Biochemistry , University of California, Los Angeles , California 90095 , USA . Email: jung@chem.ucla.edu.
  • Hernandez SP; Department of Molecular and Medical Pharmacology , University of California, Los Angeles , California 90095 , USA . Email: cradu@mednet.ucla.edu.
  • Song J; Ahmanson Translational Imaging Division , University of California, Los Angeles , California 90095 , USA.
  • Li J; Department of Chemistry and Biochemistry , University of California, Los Angeles , California 90095 , USA . Email: jung@chem.ucla.edu.
  • Turlik A; Department of Molecular and Medical Pharmacology , University of California, Los Angeles , California 90095 , USA . Email: cradu@mednet.ucla.edu.
  • Chen X; Ahmanson Translational Imaging Division , University of California, Los Angeles , California 90095 , USA.
  • Cheng CA; Department of Molecular and Medical Pharmacology , University of California, Los Angeles , California 90095 , USA . Email: cradu@mednet.ucla.edu.
  • Chen W; Ahmanson Translational Imaging Division , University of California, Los Angeles , California 90095 , USA.
  • Mona CE; Department of Chemistry and Biochemistry , University of California, Los Angeles , California 90095 , USA . Email: jung@chem.ucla.edu.
  • Stuparu AD; Department of Molecular and Medical Pharmacology , University of California, Los Angeles , California 90095 , USA . Email: cradu@mednet.ucla.edu.
  • Vergnes L; Ahmanson Translational Imaging Division , University of California, Los Angeles , California 90095 , USA.
  • Reue K; Department of Molecular and Medical Pharmacology , University of California, Los Angeles , California 90095 , USA . Email: cradu@mednet.ucla.edu.
  • Damoiseaux R; Department of Chemistry and Biochemistry , University of California, Los Angeles , California 90095 , USA . Email: jung@chem.ucla.edu.
  • Zink JI; Department of Molecular and Medical Pharmacology , University of California, Los Angeles , California 90095 , USA . Email: cradu@mednet.ucla.edu.
  • Czernin J; Department of Molecular and Medical Pharmacology , University of California, Los Angeles , California 90095 , USA . Email: cradu@mednet.ucla.edu.
  • Donahue TR; Department of Chemistry and Biochemistry , University of California, Los Angeles , California 90095 , USA . Email: jung@chem.ucla.edu.
  • Houk KN; Department of Chemistry and Biochemistry , University of California, Los Angeles , California 90095 , USA . Email: jung@chem.ucla.edu.
  • Jung ME; Department of Chemistry and Biochemistry , University of California, Los Angeles , California 90095 , USA . Email: jung@chem.ucla.edu.
  • Radu CG; Department of Bioengineering , University of California, Los Angeles , CA 90095 , USA.
RSC Med Chem ; 11(3): 392-410, 2020 Mar 01.
Article em En | MEDLINE | ID: mdl-33479645
ABSTRACT
A potent class of isoquinoline-based α-N-heterocyclic carboxaldehyde thiosemicarbazone (HCT) compounds has been rediscovered; based upon this scaffold, three series of antiproliferative agents were synthesized through iterative rounds of methylation and fluorination modifications, with anticancer activities being potentiated by physiologically relevant levels of copper. The lead compound, HCT-13, was highly potent against a panel of pancreatic, small cell lung carcinoma, prostate cancer, and leukemia models, with IC50 values in the low-to-mid nanomolar range. Density functional theory (DFT) calculations showed that fluorination at the 6-position of HCT-13 was beneficial for ligand-copper complex formation, stability, and ease of metal-center reduction. Through a chemical genomics screen, we identify DNA damage response/replication stress response (DDR/RSR) pathways, specifically those mediated by ataxia-telangiectasia and Rad3-related protein kinase (ATR), as potential compensatory mechanism(s) of action following HCT-13 treatment. We further show that the cytotoxicity of HCT-13 is copper-dependent, that it promotes mitochondrial electron transport chain (mtETC) dysfunction, induces production of reactive oxygen species (ROS), and selectively depletes guanosine nucleotide pools. Lastly, we identify metabolic hallmarks for therapeutic target stratification and demonstrate the in vivo efficacy of HCT-13 against aggressive models of acute leukemias in mice.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: RSC Med Chem Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: RSC Med Chem Ano de publicação: 2020 Tipo de documento: Article