Poster Presentation Royal Australian Chemical Institute National Congress 2026

Targeting Prolyl Hydroxylase Domain 2 (PHD2) for Stroke Therapy: From Molecular Design to Therapeutic Potential (#616)

Aya M. Soliman Yones 1 , Anthony Tumber 2 , Christopher J. Schofield 2 , Nicole Jones 3 , Luke Hunter 1
  1. School of Chemistry, University of New South Wales (UNSW) , Sydney, Australia
  2. Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Resistance, 12, Mansfield Road, Department of Chemistry, University of Oxford, OX1 3TA, United Kingdom
  3. School of Medical Sciences, University of New South Wales (UNSW), Sydney, Australia

Stroke is a major cause of mortality and lifelong disability, yet effective treatment options remain limited.1 A novel strategy that might boost the survival rate of nerve cells after a stroke, is to stimulate the brain’s natural response to hypoxia.2 To achieve this, we are seeking to inhibit a regulatory enzyme called prolyl hydroxylase domain 2 (PHD2), which serves as the “off switch” for the hypoxia response. Inhibition of PHD2 unlocks cellular survival pathways and unleashes a cascade of neuroprotection mechanisms, representing a compelling therapeutic approach for stroke intervention.3

Previous pharmacophore and docking studies in the Hunter group identified two novel PHD2 inhibitors, VH-8 and VH-16, which both demonstrated neuroprotective activity when administered as pre-treatments.4 However, these lead compounds exhibit limited blood–brain barrier (BBB) permeability, restricting their therapeutic applicability. To address this limitation, we have rationally designed and synthesized a series of next-generation analogues based on the structural framework of VH-8 and VH-16, which are predicted to maintain PHD2 inhibitory activity while offering enhanced BBB permeability.

This work provides valuable insights into the development of targeted therapeutics for stroke treatment and establishes a foundation for further biological evaluation and optimization of PHD2 inhibitors as potential clinical candidates.

  1. Feske, S. K., Am. J. Med. 2021, 134, 1457.
  2. Cramer, S. C., J. Stroke 2018, 20, 57.
  3. Ke, Q.; Costa, M., Mol. Pharmacol. 2006, 70(5), 1469-80.
  4. Richardson, N. L.; O’Malley, L. J.; Weissberger, D.; Tumber, A.; Schofield, C. J.; Griffith, R.; Jones, N. M.; Hunter, L., Bioorg. Med. Chem. 2021, 38, 116115.