Publications by authors named "James Holt-Martyn"
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.
View Article and Find Full Text PDFThe human 2-oxoglutarate (2OG)- and Fe(ii)-dependent oxygenases factor inhibiting hypoxia-inducible factor-α (FIH) and HIF-α prolyl residue hydroxylases 1-3 (PHD1-3) regulate the response to hypoxia in humans catalysing hydroxylation of the α-subunits of the hypoxia-inducible factors (HIFs). Small-molecule PHD inhibitors are used for anaemia treatment; by contrast, few selective inhibitors of FIH have been reported, despite their potential to regulate the hypoxic response, either alone or in combination with PHD inhibition. We report molecular, biophysical, and cellular evidence that the -hydroxythiazole scaffold, reported to inhibit PHD2, is a useful broad spectrum 2OG oxygenase inhibitor scaffold, the inhibition potential of which can be tuned to achieve selective FIH inhibition.
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- The study focuses on the inhibition of JMJD6, an oxygenase linked to cancer, using 2-oxoglutarate mimics and competitors, including existing drugs and drug candidates.
- Researchers utilized NMR to observe how inhibitors bind to JMJD6 and mass spectrometry to track its lysine hydroxylation activity.
- Findings indicate that certain prolyl hydroxylase inhibitors also affect JMJD6, which could aid in creating selective inhibitors for oxygenases like JMJD6 in cancer therapy.
Article Synopsis
- Human prolyl-hydroxylases (PHDs) are enzymes that detect low oxygen levels and help regulate gene expression related to hypoxia, which is crucial for treating conditions like anemia and ischemia.
- Molidustat, a newly approved PHD inhibitor, is used to treat renal anemia, and its unique structure lacks a common glycinamide side chain found in other inhibitors.
- Recent crystal structure studies of Molidustat and IOX4 with PHD2 reveal how their chemical components interact with the enzyme, highlighting differences in key amino acid conformations that affect how the enzyme binds substrates and releases products.
Article Synopsis
- The text discusses 2-oxoglutarate-dependent hypoxia inducible factor prolyl hydroxylases (PHDs) as potential targets for treating diseases like anaemia.
- It mentions that one PHD inhibitor is already approved for renal anaemia treatment, with others undergoing late-stage clinical trials.
- The authors highlight their research on the structure-activity relationship and crystallographic studies of a new class of PHD inhibitors containing 4-hydroxypyrimidine.
Article Synopsis
- * PHD inhibitors are currently in clinical trials, but there is a lack of diverse templates for effective inhibition.
- * This study identifies spiro[4.5]decanones as promising templates for developing strong and selective inhibitors of 2OG oxygenases, supported by structure-activity relationship and crystallographic analysis.
Article Synopsis
- * The study compares four PHD inhibitors in clinical trials, detailing their mechanisms, how effectively they inhibit the enzymes, and their selectivity for different enzyme subfamilies.
- * Crystallographic and NMR studies reveal variations in how these inhibitors bind to the enzymes, while cell studies show they similarly upregulate HIF target genes but differ in how quickly they act and the degree to which they inhibit hydroxylation of specific regions of the HIF protein.
Hypercholesterolemia remains one of the leading risk factors for the development of cardiovascular disease. Many large double-blind studies have demonstrated that lowering low-density lipoprotein (LDL) cholesterol using a statin can reduce the risk of having a cardiovascular event by approximately 30%. However, despite the success of statins, some patient populations are unable to lower their LDL cholesterol to meet the targeted lipid levels, due to compliance or potency issues.
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- Oxygen levels in human cells are detected by enzymes that modify proteins related to hypoxia-inducible factors (HIF).
- These HIF hydroxylases are targeted by new small molecule inhibitors to enhance HIF activity and treat conditions like anaemia.
- The paper discusses the scientific rationale behind this therapeutic approach, including design considerations for inhibitors and insights from clinical studies.
As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e.
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