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MedKoo Cat#: 202350 | Name: PX-478 HCl
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

PX-478 is an orally active small molecule that inhibits hypoxia-inducible factor 1-alpha (HIF1A) expression, potentially leading to decreased expression of genes important for tumor growth, reduced tumor cell proliferation, and induced apoptosis. Its mechanism of action is independent of VHL and p53 tumor suppressor genes and may involve glucose uptake and metabolism disruption through Glut-1 inhibition. PX-478 demonstrates excellent activity against human tumor xenografts, resulting in tumor regressions and growth delays correlated with HIF-1 levels.

Chemical Structure

PX-478 HCl
PX-478 HCl
CAS#685898-44-6 (HCl)

Theoretical Analysis

MedKoo Cat#: 202350

Name: PX-478 HCl

CAS#: 685898-44-6 (HCl)

Chemical Formula: C13H20Cl4N2O3

Exact Mass: 0.0000

Molecular Weight: 394.11

Elemental Analysis: C, 39.62; H, 5.12; Cl, 35.98; N, 7.11; O, 12.18

Price and Availability

Size Price Availability Quantity
10mg USD 110.00 Ready to ship
25mg USD 250.00 Ready to ship
50mg USD 350.00 Ready to ship
100mg USD 550.00 Ready to ship
200mg USD 950.00 Ready to ship
500mg USD 1,650.00 Ready to ship
1g USD 2,850.00 Ready to ship
2g USD 4,450.00 Ready to ship
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Related CAS #
685898-44-6 (HCl) 685847-78-3 (free base)
Synonym
PX 478; PX-478; PX 478; PX478 HCl.
IUPAC/Chemical Name
(S)-4-(2-amino-2-carboxyethyl)-N,N-bis(2-chloroethyl)aniline oxide dihydrochloride
InChi Key
GIGCDIVNDFQKRA-LTCKWSDVSA-N
InChi Code
InChI=1S/C13H18Cl2N2O3.2ClH/c14-5-7-17(20,8-6-15)11-3-1-10(2-4-11)9-12(16)13(18)19;;/h1-4,12H,5-9,16H2,(H,18,19);2*1H/t12-;;/m0../s1
SMILES Code
ClCC[N+](CCCl)([O-])C1=CC=C(C[C@H](N)C(O)=O)C=C1.[H]Cl.[H]Cl
Appearance
Brown solid powder (wax-like solid or semi-solid after absorb moisture from air). PX478 HCl is highly hygroscopic, and may become wax-like material after exposing in air, which will not impact the stability.
Purity
>95% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, DMF, ethanol, and water
Shelf Life
>5 years if stored properly
Drug Formulation
This drug may be formulated in PBS buffer. For long term stability consideration, we recommend to prepare PX478 stock solution in pH 4.0 buffer. The stock solution may be diluted by PBS before using.
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
  Stability of PX-478:  According to researchers from ProlX Pharmaceuticals, chemical stability of PX-478 under variable temperature and light conditions showed 100% recovery for greater than 6 months. PX-478, as either an amorphous or crystalline hydrochloride salt is highly water soluble. Examination of pH stability provided evidence of base lability, however excellent stability in solutions of pH<3 with t1/2 of 26 to 2643 days at 4°C. Neutral, isotonic buffered dosing solution had sufficient stability to allow i.v. administration for the toxicology and kinetics studies in mice, rats, and dogs where the maximum tolerable dose for five day i.v. treatment was found to be 100, 35 and 20mg/kg, respectively.  (source: http://aacrmeetingabstracts.org/cgi/content/abstract/2004/1/486-b).   Activity observed in animal model study: PX-478 has been shown to have efficacy against a number of human cancer xenograft models, with significant regressions and growth delays in OvCar-3 (ovarian), SHP-77 (small cell lung), PC-3 (prostate), DU-145 (prostate), MCF-7 (breast), and Caki-1 (renal). PX-478 suppresses constitutive and hypoxia induced levels of HIF-1a in cancer cells, while leaving other ubiquitin regulated proteins unaffected. Through HIF-1a inhibition , PX-478 inhibits the expression of VEGF and the glucose transporter Glut-1, resulting in massive tumour apoptosis When tumours (xenograft models in mice) are being treated with PX-478, the efficiency of tumour killing correlates with inherent tumour HIF-1a expression. (source: http://pharmalicensing.com).   Toxicity of PX-478: The primary toxicological indicators were myelosuppression and rapidly reversible weight loss that correlated with food intake. The bioanalytic protocol and assay developed for identification of PX-478 and metabolites in biological samples demonstrated excellent frozen and refrigerated stability of PX-478 once isolated.  Oral and i.p. administration of PX-478 to mice show excellent bioavailability of 86% and 91%, respectively. The terminal half life values for parent drug were determined in mice and dogs to be 60 minutes and 8 minutes, respectively. Clearance and volume of distribution in mice and dogs were found to be 4.7 and 15.6 ml/min/kg and 380 and 184 ml/kg, respectively. Protein binding studies of PX-478 in mice showed no measurable binding.  (source: http://aacrmeetingabstracts.org/cgi/content/abstract/2004/1/486-b).   Mechanism of P-478: PX-478 is the N-oxide form of the approved anticancer drug  melphalan,   PX-478 was reported to suppress HIF-1α levels in human tumor xenografts and inhibit the expression of HIF-1 target genes including vascular endothelial growth factor (VEGF) and the glucose transporter-1. PX-478 had marked antitumor activity against even large tumor xenografts, which correlated positively with HIF-1α levels. Even though the upstream targets have not been fully elucidated, PX-478 inhibited HIF-1α at multiple levels that together or individually might contribute to its antitumor activity against HIF-1α-expressing tumors. It was reported that PX-478 inhibited HIF- 1α protein levels and HIF-1 transactivating activity in a variety of cancer cell lines. The inhibition occurred in both normoxic and hypoxic conditions and did not require pVHL or p53.    Three mechanisms were identified as contributing to the decrease in HIF-1α levels by PX-478: reduction in HIF-1α mRNA levels, and inhibition of HIF-1α translation play major roles; inhibition of HIF-1α deubiquitination, appears to play a minor role. HIF-1α was up-regulated in irradiated tumors and thus might serve as a promising target for radiosensitization. PX-478 reduced HIF-1α protein levels and signaling in vitro in a dose-dependent manner and provided direct radiosensitization of hypoxic cancer cells in clonogenic survival assays using C6 glioma, HN5 and UMSCCa10 squamous cells, and Panc-1 pancreatic adenocarcinoma cell lines.   Of note, PX-478 yielded striking in vivo tumor sensitization to a single-dose irradiation, prevented postradiation HIF-1 signaling, and abrogated downstream stromal adaptation in C6 and HN5 reporter xenografts. (source: Lee K, Kim HM. A novel approach to cancer therapy using PX-478 as a HIF-1α inhibitor. Arch Pharm Res. 2011 Oct;34(10):1583-5. )   Phase I trials of P-478:  A Phase I trial was done at two sites in the US and the result was reported at the 2010 ASCO Annual Meeting. The Phase I trial of PX-478 was an open-label, dose escalation trial in 41 patients with advanced cancer that was designed to examine safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity. PX-478 was administered orally on days 1-5 of a 21 day cycle at doses ranging from 1 mg/ m2 to 88.2 mg/m2. Adverse events occurring in more than 10 percent of patients were nausea, fatigue, diarrhea and vomiting. One patient experienced prolonged Grade 3 thrombocytopenia at the highest dose level. Thirteen of 37 evaluable patients (35%) had stable disease. Pharmacodynamic studies revealed dose-proportional inhibition of HIF-1α levels. Pharmacokinetic studies demonstrated low levels of PX-478 with evidence for conversion to melphalan and other metabolites. The result was promising in that clinical treatment with PX-478 was associated with a relatively high proportion of patients achieving stable disease and a dose-dependent inhibition of HIF-1α. Metabolite identification and related metabolism studies might be done to identify metabolic pathways and active entities from PX-478 besides inactive melphalan.  Conclusively, HIF-1α was proven to be a valid target of cancer therapy and modulates multiple tumorigenic processes. The information from preclinical and clinical trials of PX-478 will be useful for developing a novel approach to cancer therapy with HIF-1α inhibitors and give positive impacts to following developments and appilications of HIF inhibitors.  (source: Lee K, Kim HM. A novel approach to cancer therapy using PX-478 as a HIF-1α inhibitor. Arch Pharm Res. 2011 Oct;34(10):1583-5. )      
Biological target:
PX-478 suppresses both constitutive and hypoxia-induced levels of HIF-1α in cancer cells, resulting in reduced expression of HIF-1α target genes. It induces apoptosis in human tumor xenografts in mice to an extent that is proportional to initial HIF-1α level. PX-478 can also increase chemo- or radiosensitivity of tumors.
In vitro activity:
This study assessed the role of PX-478 in regulating the migration of lung adenocarcinoma A549 cells under hypoxic conditions. PX-478 inhibited the migration of A549 cells induced by hypoxia and down-regulated the expression of SREBP-1. The levels of ACC1 mRNA and SREBP-1 mRNA were decreased after A549 cells treated with hypoxia combined with PX-478 for 24 hours. Reference: Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2022 Jan;38(1):68-74. Chinese. https://pubmed.ncbi.nlm.nih.gov/35634673/
In vivo activity:
In a human tumor xenograft murine model, PX-478 effectively suppressed HIF-1alpha levels in HT-29 human colon cancer xenografts, resulting in the inhibition of HIF-1 target genes (such as vascular endothelial growth factor and glucose transporter-1). PX-478 exhibited significant antitumor effects against a range of human tumor xenografts, including small cell lung cancer, colon, prostate, breast, renal, and pancreatic cancers and demonstrated regression in larger prostate tumors. Reference: Mol Cancer Ther. 2004 Mar;3(3):233-44. https://pubmed.ncbi.nlm.nih.gov/15026543/
Solvent mg/mL mM
Solubility
DMSO 62.3 158.15
DMF 30.0 76.12
Ethanol 42.7 108.27
Water 78.5 199.18
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 394.11 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
1. Jin JH, Zhao BS, Liu YZ. [Research on the mechanism of hypoxia promoting the migration of lung adenocarcinoma A549 cells]. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2022 Jan;38(1):68-74. Chinese. doi: 10.12047/j.cjap.6200.2022.013. PMID: 35634673. 2. Turhan A, Pereira MT, Schuler G, Bleul U, Kowalewski MP. Hypoxia-inducible factor (HIF1alpha) inhibition modulates cumulus cell function and affects bovine oocyte maturation in vitro†. Biol Reprod. 2021 Feb 11;104(2):479-491. doi: 10.1093/biolre/ioaa196. PMID: 33095229; PMCID: PMC7876663. 3. Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2004 Mar;3(3):233-44. PMID: 15026543. 4. Jacoby JJ, Erez B, Korshunova MV, Williams RR, Furutani K, Takahashi O, Kirkpatrick L, Lippman SM, Powis G, O'Reilly MS, Herbst RS. Treatment with HIF-1alpha antagonist PX-478 inhibits progression and spread of orthotopic human small cell lung cancer and lung adenocarcinoma in mice. J Thorac Oncol. 2010 Jul;5(7):940-9. doi: 10.1097/JTO.0b013e3181dc211f. PMID: 20512076; PMCID: PMC3782111.
In vitro protocol:
1. Jin JH, Zhao BS, Liu YZ. [Research on the mechanism of hypoxia promoting the migration of lung adenocarcinoma A549 cells]. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2022 Jan;38(1):68-74. Chinese. doi: 10.12047/j.cjap.6200.2022.013. PMID: 35634673. 2. Turhan A, Pereira MT, Schuler G, Bleul U, Kowalewski MP. Hypoxia-inducible factor (HIF1alpha) inhibition modulates cumulus cell function and affects bovine oocyte maturation in vitro†. Biol Reprod. 2021 Feb 11;104(2):479-491. doi: 10.1093/biolre/ioaa196. PMID: 33095229; PMCID: PMC7876663.
In vivo protocol:
1. Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2004 Mar;3(3):233-44. PMID: 15026543. 2. Jacoby JJ, Erez B, Korshunova MV, Williams RR, Furutani K, Takahashi O, Kirkpatrick L, Lippman SM, Powis G, O'Reilly MS, Herbst RS. Treatment with HIF-1alpha antagonist PX-478 inhibits progression and spread of orthotopic human small cell lung cancer and lung adenocarcinoma in mice. J Thorac Oncol. 2010 Jul;5(7):940-9. doi: 10.1097/JTO.0b013e3181dc211f. PMID: 20512076; PMCID: PMC3782111.
1: Lee K, Kim HM. A novel approach to cancer therapy using PX-478 as a HIF-1α inhibitor. Arch Pharm Res. 2011 Oct;34(10):1583-5. doi: 10.1007/s12272-011-1021-3. Review. PubMed PMID: 22076756. 2: Schwartz DL, Bankson JA, Lemos R Jr, Lai SY, Thittai AK, He Y, Hostetter G, Demeure MJ, Von Hoff DD, Powis G. Radiosensitization and stromal imaging response correlates for the HIF-1 inhibitor PX-478 given with or without chemotherapy in pancreatic cancer. Mol Cancer Ther. 2010 Jul;9(7):2057-67. doi: 10.1158/1535-7163.MCT-09-0768. Epub 2010 Jun 29. PubMed PMID: 20587661; PubMed Central PMCID: PMC2935253. 3: Jacoby JJ, Erez B, Korshunova MV, Williams RR, Furutani K, Takahashi O, Kirkpatrick L, Lippman SM, Powis G, O'Reilly MS, Herbst RS. Treatment with HIF-1alpha antagonist PX-478 inhibits progression and spread of orthotopic human small cell lung cancer and lung adenocarcinoma in mice. J Thorac Oncol. 2010 Jul;5(7):940-9. doi: 10.1097/JTO.0b013e3181dc211f. PubMed PMID: 20512076; PubMed Central PMCID: PMC3782111. 4: Schwartz DL, Powis G, Thitai-Kumar A, He Y, Bankson J, Williams R, Lemos R, Oh J, Volgin A, Soghomonyan S, Nishii R, Alauddin M, Mukhopadhay U, Peng Z, Bornmann W, Gelovani J. The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects. Mol Cancer Ther. 2009 Apr;8(4):947-58. doi: 10.1158/1535-7163.MCT-08-0981. PubMed PMID: 19372568; PubMed Central PMCID: PMC2908257. 5: Palayoor ST, Mitchell JB, Cerna D, Degraff W, John-Aryankalayil M, Coleman CN. PX-478, an inhibitor of hypoxia-inducible factor-1alpha, enhances radiosensitivity of prostate carcinoma cells. Int J Cancer. 2008 Nov 15;123(10):2430-7. doi: 10.1002/ijc.23807. PubMed PMID: 18729192. 6: Koh MY, Spivak-Kroizman T, Venturini S, Welsh S, Williams RR, Kirkpatrick DL, Powis G. Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2008 Jan;7(1):90-100. doi: 10.1158/1535-7163.MCT-07-0463. PubMed PMID: 18202012. 7: Jordan BF, Black K, Robey IF, Runquist M, Powis G, Gillies RJ. Metabolite changes in HT-29 xenograft tumors following HIF-1alpha inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo. NMR Biomed. 2005 Nov;18(7):430-9. PubMed PMID: 16206237. 8: Jordan BF, Runquist M, Raghunand N, Baker A, Williams R, Kirkpatrick L, Powis G, Gillies RJ. Dynamic contrast-enhanced and diffusion MRI show rapid and dramatic changes in tumor microenvironment in response to inhibition of HIF-1alpha using PX-478. Neoplasia. 2005 May;7(5):475-85. PubMed PMID: 15967100; PubMed Central PMCID: PMC1501160. 9: Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2004 Mar;3(3):233-44. PubMed PMID: 15026543.  
1. Kasai K, Segawa R, Onodera R, Asakawa S, Hiratsuka M, Hirasawa N. Lactate released from human fibroblasts enhances Ni elution from Ni plate. Toxicology. 2021 Apr 15;453:152723. doi: 10.1016/j.tox.2021.152723. Epub 2021 Feb 14. PMID: 33596451. 2. Wang Q, Zhou J, Wang X, Xu Y, Liang Z, Gu X, He C. Coupling induction of osteogenesis and type H vessels by pulsed electromagnetic fields in ovariectomy-induced osteoporosis in mice. Bone. 2022 Jan;154:116211. doi: 10.1016/j.bone.2021.116211. Epub 2021 Sep 22. PMID: 34560308. 3. Zhao T, Ren H, Jia L, Chen J, Xin W, Yan F, Li J, Wang X, Gao S, Qian D, Huang C, Hao J. Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma. Oncotarget. 2015 Feb 10;6(4):2250-62. doi: 10.18632/oncotarget.2948. Erratum in: Oncotarget. 2019 Sep 17;10(53):5569-5570. PMID: 25544770; PMCID: PMC4385849. 4. 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Toxicology. 2018 Feb 15;395:45-53. doi: 10.1016/j.tox.2018.01.006. Epub 2018 Jan 31. PMID: 29355601. 11. Bakirtzi K, West G, Fiocchi C, Law IK, Iliopoulos D, Pothoulakis C. The neurotensin-HIF-1α-VEGFα axis orchestrates hypoxia, colonic inflammation, and intestinal angiogenesis. Am J Pathol. 2014 Dec;184(12):3405-14. doi: 10.1016/j.ajpath.2014.08.015. Epub 2014 Oct 7. PMID: 25307345; PMCID: PMC4258496. 12. Park H, Lee DS, Yim MJ, Choi YH, Park S, Seo SK, Choi JS, Jang WH, Yea SS, Park WS, Lee CM, Jung WK, Choi IW. 3,3'-Diindolylmethane inhibits VEGF expression through the HIF-1α and NF-κB pathways in human retinal pigment epithelial cells under chemical hypoxic conditions. Int J Mol Med. 2015 Jul;36(1):301-8. doi: 10.3892/ijmm.2015.2202. Epub 2015 May 5. PMID: 25955241. 13. Feldhoff LM, Rueda CM, Moreno-Fernandez ME, Sauer J, Jackson CM, Chougnet CA, Rupp J. IL-1β induced HIF-1α inhibits the differentiation of human FOXP3+ T cells. Sci Rep. 2017 Mar 28;7(1):465. doi: 10.1038/s41598-017-00508-x. PMID: 28352109; PMCID: PMC5428734. 14. Kasai K, Segawa R, Onodera R, Asakawa S, Hiratsuka M, Hirasawa N. Lactate released from human fibroblasts enhances Ni elution from Ni plate. Toxicology. 2021 Apr 15;453:152723. doi: 10.1016/j.tox.2021.152723. Epub 2021 Feb 14. PMID: 33596451. 15. Ikeda S, Kitadate A, Abe F, Saitoh H, Michishita Y, Hatano Y, Kawabata Y, Kitabayashi A, Teshima K, Kume M, Takahashi N, Tagawa H. Hypoxia-inducible microRNA-210 regulates the DIMT1-IRF4 oncogenic axis in multiple myeloma. Cancer Sci. 2017 Apr;108(4):641-652. doi: 10.1111/cas.13183. Epub 2017 Apr 20. PMID: 28164410; PMCID: PMC5406542. 16. Wang L, Fan J, Yan CY, Ling R, Yun J. Activation of hypoxia-inducible factor-1α by prolonged in vivo hyperinsulinemia treatment potentiates cancerous progression in estrogen receptor-positive breast cancer cells. Biochem Biophys Res Commun. 2017 Sep 16;491(2):545-551. doi: 10.1016/j.bbrc.2017.03.128. Epub 2017 Mar 25. PMID: 28351619. 17. Penumatsa KC, Toksoz D, Warburton RR, Hilmer AJ, Liu T, Khosla C, Comhair SA, Fanburg BL. Role of hypoxia-induced transglutaminase 2 in pulmonary artery smooth muscle cell proliferation. Am J Physiol Lung Cell Mol Physiol. 2014 Oct 1;307(7):L576-85. doi: 10.1152/ajplung.00162.2014. Epub 2014 Aug 15. PMID: 25128524; PMCID: PMC4187037. 18. Ha JH, Radhakrishnan R, Jayaraman M, Yan M, Ward JD, Fung KM, Moxley K, Sood AK, Isidoro C, Mukherjee P, Song YS, Dhanasekaran DN. LPA Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response. Cancer Res. 2018 Apr 15;78(8):1923-1934. doi: 10.1158/0008-5472.CAN-17-1624. Epub 2018 Jan 31. PMID: 29386184; PMCID: PMC5899640. 19. Sakai Y, Kassai H, Nakayama H, Fukaya M, Maeda T, Nakao K, Hashimoto K, Sakagami H, Kano M, Aiba A. Hyperactivation of mTORC1 disrupts cellular homeostasis in cerebellar Purkinje cells. Sci Rep. 2019 Feb 26;9(1):2799. doi: 10.1038/s41598-019-38730-4. PMID: 30808980; PMCID: PMC6391425. 20. Bakirtzi K, West G, Fiocchi C, Law IK, Iliopoulos D, Pothoulakis C. The neurotensin-HIF-1α-VEGFα axis orchestrates hypoxia, colonic inflammation, and intestinal angiogenesis. Am J Pathol. 2014 Dec;184(12):3405-14. doi: 10.1016/j.ajpath.2014.08.015. Epub 2014 Oct 7. PMID: 25307345; PMCID: PMC4258496. 21. Kim D, Dai J, Park YH, Fai LY, Wang L, Pratheeshkumar P, Son YO, Kondo K, Xu M, Luo J, Shi X, Zhang Z. Activation of Epidermal Growth Factor Receptor/p38/Hypoxia-inducible Factor-1α Is Pivotal for Angiogenesis and Tumorigenesis of Malignantly Transformed Cells Induced by Hexavalent Chromium. J Biol Chem. 2016 Jul 29;291(31):16271-81. doi: 10.1074/jbc.M116.715797. Epub 2016 May 25. Retraction in: J Biol Chem. 2019 Oct 18;294(42):15558. PMID: 27226640; PMCID: PMC4965575. 22. 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