Discovery of neuroprotective agents that inhibit human prolyl hydroxylase PHD2

Richardson, Nicole L.; O'Malley, Laura J.; Weissberger, Daniel; Tumber, Anthony; Schofield, Christopher J.; Griffith, Renate; Jones, Nicole M.; Hunter, Luke

doi:10.1016/j.bmc.2021.116115

Cited by 4 publications

(2 citation statements)

References 53 publications

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“…To date, many PHD2 inhibitors have been reported, − and among them, six have been approved, including Roxadustat, Vadadustat, Daprodustat, Enarodustat, Molidustat, and Desidustat (Table S1). On December 18, 2018, the first-in-class PHD inhibitor Roxadustat ( 1a ) (Figure A), developed by FibroGen, was approved by the National Medical Products Administration (NMPA) in China .…”

Section: Introductionmentioning

confidence: 99%

Preferred Conformation-Guided Discovery of Potent and Orally Active HIF Prolyl Hydroxylase 2 Inhibitors for the Treatment of Anemia

Zhang

Sun

et al. 2023

J. Med. Chem.

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In this work, we discovered a novel series of prolyl hydroxylase 2 (PHD2) inhibitors with improved metabolic properties based on a preferred conformation-guided drug design strategy. Piperidinyl-containing linkers with preferred metabolic stability were designed to match the dihedral angle of the desired docking conformation in the PHD2 binding site with the lowest energy conformation. Based on the piperidinyl-containing linkers, a series of PHD2 inhibitors with high PHD2 affinity and favorable druggability were obtained. Remarkably, compound 22, with an IC 50 of 22.53 nM toward PHD2, significantly stabilized hypoxia-inducible factor α (HIFα) and upregulated the expression of erythropoietin (EPO). Furthermore, oral administration of 22 dose-dependently stimulated erythropoiesis in vivo. Preliminary preclinical studies showed that 22 has good pharmacokinetic properties and an excellent safety profile, even at 10 times the efficacious dose (200 mg/kg). Taken together, these results indicate that 22 is a promising candidate for anemia treatment.

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Section: Introductionmentioning

confidence: 99%

Preferred Conformation-Guided Discovery of Potent and Orally Active HIF Prolyl Hydroxylase 2 Inhibitors for the Treatment of Anemia

Zhang

Sun

et al. 2023

J. Med. Chem.

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“…Hypoxic conditions reduce PHD activity allowing HIFs-α to escape pVHL recognition. HIFs-α accumulate in the cytosol and translocate to the nucleus, where they dimerize with HIF-1β to regulate the transcription of multiple genes involved in hypoxia adaptive response, including the vascular endothelial growth factor (VEGF), erythropoietin (EPO), pyruvate dehydrogenase kinase-1 (PDK1), and glucose transporter-1 (GLUT-1) [16,17]. Although the PHDs are mostly inhibited in hypoxia, their activity is still observed at low oxygen levels, highlighting their sensitivity to changes in oxygen availability and their role as cellular oxygen sensors [18,19].…”

Section: Introductionmentioning

confidence: 99%

Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations

Camagni

Minervini

Tosatto

2023

IJMS

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The Prolyl Hydroxylases (PHDs) are an enzymatic family that regulates cell oxygen-sensing. PHDs hydroxylate hypoxia-inducible transcription factors α (HIFs-α) driving their proteasomal degradation. Hypoxia inhibits PHDs activity, inducing HIFs-α stabilization and cell adaptation to hypoxia. As a hallmark of cancer, hypoxia promotes neo-angiogenesis and cell proliferation. PHD isoforms are thought to have a variable impact on tumor progression. All isoforms hydroxylate HIF-α (HIF-1,2,3α) with different affinities. However, what determines these differences and how they pair with tumor growth is poorly understood. Here, molecular dynamics simulations were used to characterize the PHD2 binding properties in complexes with HIF-1α and HIF-2α. In parallel, conservation analysis and binding free energy calculations were performed to better understand PHD2 substrate affinity. Our data suggest a direct association between the PHD2 C-terminus and HIF-2α that is not observed in the PHD2/HIF-1α complex. Furthermore, our results indicate that phosphorylation of a PHD2 residue, Thr405, causes a variation in binding energy, despite the fact that this PTM has only a limited structural impact on PHD2/HIFs-α complexes. Collectively, our findings suggest that the PHD2 C-terminus may act as a molecular regulator of PHD’s activity.

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New sesquiterpenoids with neuroprotective effects in vitro and in vivo from the Picrasma chinensis

Fan,

Song,

Shi

et al. 2024

Fitoterapia

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Discovery of neuroprotective agents that inhibit human prolyl hydroxylase PHD2

Cited by 4 publications

References 53 publications

Preferred Conformation-Guided Discovery of Potent and Orally Active HIF Prolyl Hydroxylase 2 Inhibitors for the Treatment of Anemia

Preferred Conformation-Guided Discovery of Potent and Orally Active HIF Prolyl Hydroxylase 2 Inhibitors for the Treatment of Anemia

Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations

New sesquiterpenoids with neuroprotective effects in vitro and in vivo from the Picrasma chinensis

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