Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials

Yeh, Tzu‐Lan; Leissing, T.M.; Abboud, Martine I.; Thinnes, Cyrille C.; Atasoylu, Onur; Holt‐Martyn, James P.; Zhang, Dong; Tumber, Anthony; Lippl, Kerstin; Lohans, Christopher T.; Leung, Ivanhoe K. H.; Morcrette, Helen; Clifton, I.J.; Claridge, Timothy D. W.; Kawamura, Akane; Flashman, Emily; Lü, Xin; Ratcliffe, Peter J.; Chowdhury, Rasheduzzaman; Pugh, Christopher W.; Schofield, Christopher J.

doi:10.1039/c7sc02103h

Cited by 195 publications

(329 citation statements)

References 94 publications

(151 reference statements)

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“…Previous analyses in cells described DMOG and DIP as pan‐His, FG‐4592, GSK1278863, BAY85‐3934, AKB‐6548, FG‐2216, DFX, and IOX2 as selective for PHDs, and DM‐NOFD as FIH‐selective . Using our novel cell‐based assay, we reproduced the reported HI selectivities except for DFX (pan‐HI in our assay) and DM‐NOFD (no FIH inhibition in our OTUB1 assay) (Supplemental Figure S2).…”

Section: Resultssupporting

confidence: 76%

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

et al. 2019

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factor; HRB5rl, human hepatoma Hep3B cells stably transfected with the HIF-dependent Firefly luciferase reporter pH3SVL followed by the Renilla reporter construct pRL-SV40; JNJ-1935, JNJ-42041935; OTUB1, ovarian tumor domain-containing ubiquitin aldehyde binding protein 1; PHD, prolyl-4-hydroxylase domain; SDR, SensorDish Reader; SV40, simian virus 40; 2OG, 2-oxoglutarate. AbstractPharmacologic HIF hydroxylase inhibitors (HIs) are effective for the treatment of anemia in chronic kidney disease patients and may also be beneficial for the treatment of diseases such as chronic inflammation and ischemia-reperfusion injury. The selectivities of many HIs for HIF hydroxylases and possible off-target effects in cellulo are unclear, delaying the translation from preclinical studies to clinical trials. We developed a novel assay that discriminates between the inhibition of HIF-α prolyl-4-hydroxylase domain (PHD) enzymes and HIF-α asparagine hydroxylase factor inhibiting HIF (FIH). We characterized 15 clinical and preclinical HIs, categorizing them into pan-HIF-α hydroxylase (broad spectrum), PHD-selective, and FIHselective inhibitors, and investigated their effects on HIF-dependent transcriptional regulation, erythropoietin production, and cellular energy metabolism. While energy homeostasis was generally maintained following HI treatment, the pan-HIs led to a stronger increase in pericellular pO 2 than the PHD/FIH-selective HIs. Combined knockdown of FIH and PHD-selective inhibition did not further increase pericellular pO 2 . Hence, the additional increase in pericellular pO 2 by pan-over PHD-selective HIs likely reflects HIF hydroxylase independent off-target effects. Overall, these analyses demonstrate that HIs can lead to oxygen redistribution within the cellular microenvironment, which should be considered as a possible contributor to HI effects in the treatment of hypoxia-associated diseases. K E Y W O R D Sanemia, hypoxia, 2-oxoglutarate oxygenase inhibitor, prolyl hydroxylase inhibitor, Roxadustat

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Section: Resultssupporting

confidence: 76%

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

et al. 2019

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“…By contrast, the glycinamide side chain present in many PHD2 inhibitors (including several compounds in clinical trials, e.g., 6 and 7 ) is clearly not required for potent OGFOD1 inhibition. It should also be noted that potent PHD2 inhibitors without a glycinamide side chain are known . In future work, it will be of interest to further explore the selectivity of the compounds reported here.…”

Section: Discussionmentioning

confidence: 90%

“…It is important to note that many PHD2 inhibitors reported in the literature, including those screened in this work, and those currently in clinical trials, also inhibit OGFOD1 . Indeed, they may also inhibit other human prolyl hydroxylases and 2OG oxygenases, including those for which assays are currently not available .…”

Section: Discussionmentioning

confidence: 93%

“…Analogues bearing N , N′ ‐dimethyl ( 29 ), N , N′ ‐diethyl ( 30 ), and N , N′ ‐dicyclohexyl ( 31 ) groups were prepared (Figure C); analogues 30 and 31 were less potent than 29 , suggesting that substituents larger than methyl groups may not be favorable for OGFOD1 inhibition (Figure S9). Note, however, that GSK1278863 6 potently inhibits OGFOD1 despite the presence of N , N′ ‐dicyclohexyl groups (Figure A) …”

Section: Resultsmentioning

confidence: 99%

“…NI: no inhibition observed. (B) Western blot (antibody specific for HIFα) showing the lack of impact of CCT3 and CCT4 on the activity of PHD enzymes in HeLa cells . In comparison, the known PHD inhibitor IOX4 inhibits the hydroxylation of HIFα, preventing proteasomal degradation .…”

Section: Resultsmentioning

confidence: 99%

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Selective Inhibitors of a Human Prolyl Hydroxylase (OGFOD1) Involved in Ribosomal Decoding

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Human prolyl hydroxylases are involved in the modification of transcription factors, procollagen, and ribosomal proteins, and are current medicinal chemistry targets. To date, there are few reports on inhibitors selective for the different types of prolyl hydroxylases. We report a structurally informed template‐based strategy for the development of inhibitors selective for the human ribosomal prolyl hydroxylase OGFOD1. These inhibitors did not target the other human oxygenases tested, including the structurally similar hypoxia‐inducible transcription factor prolyl hydroxylase, PHD2.

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A novel AMPK activator shows therapeutic potential in hepatocellular carcinoma by suppressing HIF1α‐mediated aerobic glycolysis

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Hepatocellular carcinoma (HCC) is characterized by rapid growth, early vascular invasion, and high metastasis. Currently available US Food and Drug Administration (FDA)‐approved drugs show low therapeutic efficacy, limiting HCC treatment to chemotherapy. We designed and synthesized a novel small molecule, SCT‐1015, that allosterically activated adenosine monophosphate‐activated protein kinase (AMPK) to suppress the aerobic glycolysis in HCC. SCT‐1015 was shown to bind the AMPK α and β‐subunit interface, thereby exposing the kinase α domain to the upstream kinases, resulting in the increased AMPK activity. SCT‐1015 dramatically reduced HCC cell growth in vitro and tumor growth in vivo . We further found that AMPK formed protein complexes with hypoxia‐inducible factor 1‐alpha (HIF1α) and that SCT‐1015‐activated AMPK promoted hydroxylation of HIF1α (402P and 564P), resulting in HIF1α degradation by the ubiquitin‐proteasome system. With declined HIF1α abundance, many glycolysis‐related enzymes were downregulated, suppressing aerobic glycolysis, and promoting oxidative phosphorylation. These results indicated that SCT‐1015 channeled HCC cells into an unfavorable metabolic status. Overall, we reported SCT‐1015 as a direct activator of AMPK signaling that held therapeutic potential in HCC.

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Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials

Abstract: Four compounds in clinical trials for anaemia treatment are potent inhibitors of the hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs), but differ in potency and how they interact with HIF at the PHD active site.

Cited by 195 publications

References 94 publications

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

Selective Inhibitors of a Human Prolyl Hydroxylase (OGFOD1) Involved in Ribosomal Decoding

A novel AMPK activator shows therapeutic potential in hepatocellular carcinoma by suppressing HIF1α‐mediated aerobic glycolysis

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