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    Home > Biochemistry News > Biotechnology News > A brief discussion of the regulator of low oxygen-induced factor degradation- prosytospidule hydroxylase

    A brief discussion of the regulator of low oxygen-induced factor degradation- prosytospidule hydroxylase

    • Last Update: 2020-06-08
    • Source: Internet
    • Author: User
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    Figure 1William GKaelin Jr(left), Sir Peter JRatcliffe (center), Gregg LSemenza (right), picturedthis year's NoBefore we talk about PHD, we have to talk about HIF, which Semenza et aldiscovered in 1992 is an hetero-polypolymer transcription factor consisting of an oxygen-highly sensitive factor, HIF-alpha and HIF-betaUnder hypoxia conditions, HIF-alpha and HIF-beta dipolycosis further activates the transcription factor p300 and binds to hRE, the hypoxia reaction element, to regulate a variety of gene expressions, such as red blood cell production, mitochondrial metabolism and angiogenesisIn the event of normal oxygen conditions or damage to the body, HIF-alpha can be hydroxylated by the PHD enzyme, causing it to be quickly identified by the Linsch factor VHL and degraded in ubiquity (Figure 2)Figure 2HIF signal regulation pathway (from reference 3)under normal oxygen conditions, HIF-alpha proline residues (Pro402, Pro564, Pro531, Pro490, PHD enzyme catalytic Pro564's meter constant Km is low, so Pro564 plays an important role in HIF regulation) can be PHD enzyme hydroxylation, resulting in its rapid degradation by the Linch factor VHL and ubiquitizationUnder low oxygen conditions, HIF-alpha can avoid hydroxylation, which promotes the expression of downstream related genes, such as EPO, and HIF-beta dipolyPHD enzymes mainly include PHD1, PHD2 and PHD3, of which PHD1 is mainly distributed in the nucleus, PHD2 is distributed in cytoplasm, and PHD3 cytoplasm is distributedPHD is non-hemoglobin iron (II) dependent on the peroxidase, which in the presence of oxygen, iron and 2-OG to catalyze HIF-alpha proline hydroxylation (Figure 3), hydroxyl-based HIF-alpha can be identified by VHL and rapid degradation the current research shows that PHD2 catalytic HIF-alpha hydroxylation has a clear advantage over PHD1/PHD3 Based on its endogenous ligand 2-OG, many competitive PHD2 small molecular inhibitors have been reported in recent years, which can squeeze 2-OG out of the active pocket to achieve the activity of the inhibitor PHD2 enzyme, thus stabilizing HIF levels Promote the elevated level of erythropoietin EPO hormone in the body, so as to treat chronic renal anemia and other diseases Figure 3 PHD2 crystal structure and HIF-alpha hydroxyl peptide segment (mainly Pro564-bit amino acids are degraded by hydroxylation) PHD2 development pipeline December 2018, China's National Drug Administration (NMPA) approved priority The review approval process approved the listing of the drug Rosastat capsule (product name: Arejo, INN generic name: Roxadustat) discovered by FibroGen and cooperated with Japanese drug company Astellas to treat anemia caused by chronic kidney disease (CKD) in patients undergoing dialysis treatment it is worth mentioning that China was the first country to approve Rosas, and that Rosas is the world's first new drug based on oxygen-aware regulation, and that patients with CKD anemia in China have been the first to benefit from the Nobel prize-level results, Rosastas In July 2019, Professor Chen Nan of Shanghai Jiaotong University Medical College Hospital and Professor Yu Chuanming of Huashan Hospital affiliated with Fudan University also published the results of two Phase III experiments on Rosasta in NEJM, which mainly introduced the effect of rosacea treatment in patients with long-term dialysis and anemia without dialysis with the launch of the first oral PHD2 small molecule inhibitor, Rosas, PHD2 small molecule inhibitors are in the midst of intense development A small junction is made based on PHD2 preparations currently in clinical study (see Table 1) , PHD2 small molecule inhibitors are currently competitive in the field of ckD chronic kidney anemia, and in July 2019, Akebia Therapeutics announced that its partner, Mitsubishi Tianbian, had submitted a new drug listing application for Vadadustat to treat chronic kidney anemia In August 2019, GlaxoSmithKline submitted a new drug application to Japan's Ministry of Health, Labour and Welfare for the treatment of anaemia caused by chronic kidney disease If the approval goes well, Vadadustat and Daprodustat will enter the market in 2020 domestic pharmaceutical company Dongsun PHD2 small molecule inhibitor HEC53856 in November 2018 to take the first place to obtain clinical approval, into clinical Phase I The dDO-3055, jointly developed by Professor Yu Qidong of China Pharmaceutical University and Hengrui Pharmaceuticals, also received clinical approval in April 2019 and entered clinical Phase I Sansheng Pharmaceutical's new drug number HIF-117 is also in the recent declaration of clinical approval As anti-kidney anemia drugs develop further, competition in this field will become extremely intense, which will also promote better, faster and healthier development of our pharmaceutical market, benefiting more patients with chronic kidney disease-induced anemia Table 1 PHD2 small molecule inhibitors (excluding no progress and termination drugs) company/institution column the first and coarsed for the drug moleculeof collated from the drug database 4 Representative PHD2 small molecule inhibitor chemical structure, mainly for glycinic acid structure 5 Rosastast original synthetic route (from reference 6) 6 Vadadustat Synthesis Route (from Reference 7) Figure 7 Daprodustat Synthesis Route (from Reference 6) Figure 8 Enarodustat Synthesis Route (from Reference 8) Figure 9 Molidustat synthesis route (from reference 7) conclusion HIF as a physiological oxygen control factor, the future in the anti-anemia anti-cancer potential unlimited, how to achieve better regulation of HIF level will be the main battleground of future scientists, and PHD is undoubtedly the main battleground of this battlefield, scientists have achieved a certain victory, look forward to the future can come more short-press! references: 1 Li, Z.; You, Q.; Zhang, X Small-Molecule Modulators of thexia-Inducible Factor Pathway: Development and Therapeutic Applications J Med Chem 2019, 62 (12), 5725-5749 2 Joharapurkar, A A.; Pandya, V B Prolyl Hydroxylases: A Make in TheCase of Anemia Associate s J Med Chem 2018, 61 (16), 6964-6982 3 Rabinowitz, M H Inhibition of the hypoxia-inducible factor prolyl hydroxylase domain origin sage s: tricking the body into the over-the-top and repair responses J Med Chem 2013, 56 (23), 9369-402; 4 Chen, N., Hao, C., Liu, B C., et al Roxadustat Treatment for Anemia in Patients Undercom Long-Term Dialysis N Engl J Med 2019, 381 (11), 1011-1022 5 Chen, N., Hao, C., Peng, X., et al Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis N Engl J Med 2019, 381 (11), 1001-1010 6 Drug data: https://data.pharmacodia.com
    7 Wu, Y., Wang, N., et al Small-molecules of HIF-PHD2: a valid strategy to renal anemia treatment in clinical therapy Med Chem Commun 2016,7 (7), 1271-1284 8 Ogoshi, Y., Matsui, T., Mitani, I., et al Discovery of JTZ-951: A HIF Prolyl Hydroxylase Inhibitor for the Treatment of Renal Anemia ACS Med Chem Lett 2017, 8 (12), 1320-1325 Zhang Xiaojin, Yu Qidong, Lei Yonghua, etc., the inhibitors of the acetylene-type pyridine hydroxylase, its preparation methods and medicinal uses CN10513088A 10 Zuo Yinglin, Wang Xiaojun, Zhang Shuai, et al., protalysinhydroxerase inhibitors and their uses CN108069957A Pharmaceutical Dusho app "Points New Play" Company enjoys database value permission
    September 2019 China 1 class of new drug clinical dynamics September 2019 global approval of new drug profile
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