The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia

  • Nat Cancer. 2024 Apr 18. doi: 10.1038/s43018-024-00761-w.
Hannah Lawson  #  1  2 ,  James P Holt-Martyn  #  3 ,  Vilma Dembitz  2  4 ,  Yuka Kabayama  5 ,  Lydia M Wang  1  2 ,  Aarushi Bellani  1  2 ,  Samanpreet Atwal  3 ,  Nadia Saffoon  3 ,  Jozef Durko  2 ,  Louie N van de Lagemaat  2  5 ,  Azzura L De Pace  5 ,  Anthony Tumber  3 ,  Thomas Corner  3 ,  Eidarus Salah  3 ,  Christine Arndt  3 ,  Lennart Brewitz  3 ,  Matthew Bowen  3 ,  Louis Dubusse  1  2 ,  Derek George  1  2 ,  Lewis Allen  1  2 ,  Amelie V Guitart  5  6 ,  Tsz Kan Fung  7  8 ,  Chi Wai Eric So  7  8 ,  Juerg Schwaller  9 ,  Paolo Gallipoli  2 ,  Donal O'Carroll  5 ,  Christopher J Schofield  10 ,  Kamil R Kranc  11  12
Affiliations
  • 1. The Institute of Cancer Research, London, UK.
  • 2. Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • 3. Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • 4. Department of Physiology and Immunology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia.
  • 5. Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
  • 6. Université de Bordeaux, Institut National de la Santé et de la Recherche Médicale INSERM U1035, Bordeaux, France.
  • 7. Leukemia and Stem Cell Biology Group, Comprehensive Cancer Centre, King's College London, London, UK.
  • 8. Department of Haematological Medicine, King's College Hospital, King's College London, London, UK.
  • 9. University Children's Hospital Basel (UKBB), Department of Biomedicine, University of Basel, Basel, Switzerland.
  • 10. Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK. [email protected].
  • 11. The Institute of Cancer Research, London, UK. [email protected].
  • 12. Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. [email protected].
  • # Contributed equally.
PMID: 38637657 DOI: 10.1038/s43018-024-00761-w
Abstract

Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce Apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of Bcl-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax.

Products