Novel complex crystal structure of prolyl hydroxylase domain-containing protein 2 (PHD2): 2,8-Diazaspiro[4.5]decan-1-ones as potent, orally bioavailable PHD2 inhibitors

Deng, Guanghui; Zhao, Baowei; Ma, Yingli; Xu, Qiongfeng; Wang, Hailong; Yang, Liuqing; Zhang, Qing; Guo, Taylor B.; Zhang, Wei; Jiao, Yang; Cai, Xin; Zhang, Jinqiang; Liu, Houfu; Guan, Xiao-Ming; Lu, Hongtao; Xiang, Jia‐Ning; Elliott, John D.; Lin, Xichen; Ren, Feng

doi:10.1016/j.bmc.2013.08.046

Cited by 17 publications

(22 citation statements)

References 23 publications

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“…2, S1, S2 and S4 and Table S3†). The new structure reveals that 11 makes similar interactions with PHD2 to those observed for 17 13. The 3-methyl pyridine ring of 11 penetrates into the 2OG binding pocket 7,8.…”

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confidence: 55%

“…2), and is apparently amenable to development of PHD selective and, more generally, 2OG oxygenase inhibitors 7. Limited SAR has been reported for the spiro[4.5]decanones series by Vachal et al and Deng et al , and no details for the potential of the series for selective inhibition has been described 12,13. Here we report SAR and structural studies of spiro[4.5]decanone containing PHD inhibitors ( 11–16 , 23–27 , 36–44 ).…”

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confidence: 99%

“…2). 13 Chelation of the active site metal of 2OG oxygenases by a pyridine ring is well precedented, e.g. with pyridine carboxylate inhibitors 14.…”

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confidence: 99%

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Studies on spiro[4.5]decanone prolyl hydroxylase domain inhibitors

et al. 2019

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Studies on spiro[4.5]decanone prolyl hydroxylase domain inhibitors

et al. 2019

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“…In the case of non‐carboxylic acid PHD2 inhibitor in the co‐crystal structure (PDB code: 4JZR), the bidentate chelation interaction is conserved while the salt bridge interaction with the Arg383 residue of PHD2 is missing (Figure b). In addition, this ligand was found to form several new interactions with resides opposite to the ion binding pocket of PHD2 (Deng et al, ). These interactions primarily include a π–cation interaction and a hydrogen bond with the Arg322 residue (Figure b).…”

Section: Resultsmentioning

confidence: 99%

Discovery of prolyl hydroxylase 2 inhibitors with new chemical scaffolds as in vivo active erythropoietin inducers through a combined virtual screening strategy

et al. 2019

Chem Biol Drug Des

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Hypoxia-inducible factor (HIF) is identified to be a promising target to mediate the response to hypoxia. Its stability and activation are negatively controlled by prolyl hydroxylase 2 (PHD2). Thus, PHD2 inhibition has been perceived as a promising anti-anemia therapy. In this study, we carried out a structure-based virtual screening followed by in vitro and in vivo biological validation, with the goal to identify novel PHD2 inhibitors. As a result, a set of hits with new chemical scaffolds were revealed to be active in vitro for PHD2 inhibition. Compounds 2 and 3 were revealed to be capable of stabilizing HIF-α and stimulating erythropoietin (EPO) expression in cell-based assays. Notably, further in vivo assays revealed that 2 was capable of elevating the EPO plasma levels in C57BL/6 mice model. These findings provide new chemical scaffolds for further development of PHD2 inhibitors. K E Y W O R D Santi-anemia, EPO, HIF, PHD2 inhibitor, virtual screening SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section. How to cite this article: Yu Z, Li Z, Yu Q, et al. Discovery of prolyl hydroxylase 2 inhibitors with new chemical scaffolds as in vivo active erythropoietin inducers through a combined virtual screening strategy. Chem Biol Drug Des. 2020;95:270-278.

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“…Whereas no functionality commonly associated with Nrf2 activation is present in the Nrf2-activating HDAC inhibitors, PHD is an iron-dependent dioxygenase, and the metal-coordinating hydroxamate functionality of HDACi does provide a potential mechanism for PHD inhibition and HIF-1 α stabilization. To test the potential for PHD inhibition by metal coordination, we docked the best HIF-1 stabilizing phenyl-hydroxamates into the binding site of PHD2 (4JZR) 22 as exemplified by ING-6 in Figure 3. The active site Fe(II) is tethered by His313, His374, and Asp315, and is capable of coordinating the hydroxamate carbonyl oxygen as a fourth ligand (Fe–O distance 2.15 Å), while the NH group of ING-6 forms a hydrogen bond with the nearby Asp254 residue through water molecule 538.…”

Section: Resultsmentioning

confidence: 99%

Activation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors

Gaisina

Lee

Kaidery

et al. 2018

ACS Chem. Neurosci.

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Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1α and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer's and Parkinson's diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1α and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2. Two superior tripartite agents, ING-6 and ING-66, showed neuroprotection against various cellular insults, associated with stabilization of both Nrf2 and HIF-1, and expression of their respective target genes in vitro and in vivo. Discovery of the innate ability of phenylhydroxamate HDAC inhibitors to activate Nrf2 and HIF provides a novel route to multifunctional neuroprotective agents and cautions against HDAC6 selective inhibitors as chemical probes of specific HDAC isoform function.

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Novel complex crystal structure of prolyl hydroxylase domain-containing protein 2 (PHD2): 2,8-Diazaspiro[4.5]decan-1-ones as potent, orally bioavailable PHD2 inhibitors

Cited by 17 publications

References 23 publications

Studies on spiro[4.5]decanone prolyl hydroxylase domain inhibitors

Studies on spiro[4.5]decanone prolyl hydroxylase domain inhibitors

Discovery of prolyl hydroxylase 2 inhibitors with new chemical scaffolds as in vivo active erythropoietin inducers through a combined virtual screening strategy

Activation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors

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