2. Academic Validation
  3. The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia

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

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. christopher.schofield@chem.ox.ac.uk.
  • 11 The Institute of Cancer Research, London, UK. kamil.kranc@icr.ac.uk.
  • 12 Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. kamil.kranc@icr.ac.uk.
  • # 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.

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