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Design and Evaluation of HIF-1 Inhibitors for Tumor Treatment

This study explores inhibiting HIF-1 as a strategy to treat hypoxic tumor cells. Molecular dynamics and DNA interactions of selective compounds are examined for potential use as sensitizers to chemotherapeutic agents.

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Design and Evaluation of HIF-1 Inhibitors for Tumor Treatment

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  1. Insilico design, synthesis and biological evaluation of inhibitors of hypoxia-inducible factor (HIF-1) as antitumor agents LucíaMinini, Maira De Negri, Alicia Merlino, María Laura Lavaggi. LQTC, Medicinal Group, Faculty of Sciences, University of the Republic, Uruguay

  2. Hypoxic tumor cell. • Human solid tumors are less well-oxygenated than the normal tissues from which they arose. • Tumor hypoxia leads to resistance to radiotherapy and anticancer chemotherapy as well as predisposing for increased tumor metastases. • Hypoxia induces changes in gene expression profile through the induction of transcription factors called hypoxia -inducible factors (HIF-1) Howtotreathypoxic tumor cells?

  3. Complejo Pol II HIF-1 CBP/p300 HIF-1 hipoxia HIF-1 Glucose metabolism Cell growth Angiogenesis In normoxic conditions , HIF- 1α is hydroxilated in the ODD and TAD domains, causing degradation and preventing it bind to the transcriptional co-activator p300.

  4. Hypoxia inducible factor HIF-1 • HIF-1 is a heterodimeric protein that activates transcription of cell survival -related genes. It consists of two subunits, HIF- 1α , regulated by cell oxygenation. • Because of this, it is translocated to the nucleus where it dimerizes with HIF- 1β3 , and bind to specific DNA sequences known as response elements hypoxia (HRE)

  5. Bio-reductiveprodrugs. McKeown, S.R.; Coweny, R.L.; Williams, K.J. (2007) “Bioreductive drugs: from concept to clinic”. Clinical Oncology, 19, 427-442

  6. Phenazine 5,10 dioxidesderivativesdesign. Increasedtoxicity Increasedtoxicity Aromatic amine

  7. Phenazine 5,10 dioxidesderivatives.

  8. Phenazine 5,10 dioxidesderivatives.

  9. HIF-1 Inhibitors: HRE interactiveagents

  10. HIF-1 Inhibitors: HRE interactiveagentsin progressdockingstudies. 1 2 3 4 5 6

  11. 1 2 3 4 5 6

  12. Molecular dinamics show intercalation within DNA strands.

  13. DNA INTERACTION-Fluorescence spectroscopy Stern-Volmer If0 / If = 1 + KQ [Q] KQ = (18 ± 1) x 10-3

  14. 5 6 1 DNA INTERACTION Ksv= (1,5 ± 1,3) x 10-3 Ksv= (1,0 ± 0,8) x 10-3 . 3 7 Ksv= (2,7 ± 0,8) x 10-3

  15. 2 1 DNA INTERACTION 9 Ksv= (14,3 ± 0,4) x 10-3 Ksv= (1,0 ± 0,8) x 10-3 8 Ksv= (7,3 ± 1,7) x 10-3 Ksv= (24,4 ± 2,8) x 10-3

  16. 12 13 DNA INTERACTION 10 Ksv= (10,1 ± 0,4) x 10-3 Ksv= (2,8± 0,2) x 10-3 11 Ksv= (9,3± 0,7) x 10-3 Ksv= (15,2 ± 0,8) x 10-3

  17. DNA INTERACTION 14 16 Ksv= (0,1 ± 0,2) x 10-3 Ksv= (10,7 ± 1,4) x 10-3 17 15 Ksv= (0,1 ± 0,1) x 10-3 Ksv= (8,3 ± 0,4) x 10-3

  18. Biologicalevaluation-selective active normoxiccompounds

  19. Biologicalevaluation-selective active hypoxiccompounds

  20. In vivo evaluation in progress Hystone deacetylase inhibitors

  21. Hystone deacetylase inhibitors as sensitizers to chemotherapeutic agents.

  22. Biological activity-U2O2 osteosarcoma cells.

  23. Biological activity-U2O2 osteosarcoma cells.

  24. Sensitizer effect in osteosarcoma cells.

  25. Perspectives • Determine the level of HDAC7 and HIF-1 expression in cells treated with the activecompounds under hypoxia, to determine its potential use as a hypoxic tumor cell sensitizer to other chemotherapeutic agents. • Determine HIF-1 inhibition in cells treated with selectivecompounds under hypoxia and HRE interaction.

  26. Acknowledgments: MEC, ANII, PEDECIBA-QUÍMICA. University of the Republic, Uruguay. IIBCE. Lic.LucíaMinini. Dr. Alicia Merlino Dr. Paola Hernández Bach. Maira de Negri Thank you for your attention.

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