Razuprotafib
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MedKoo CAT#: 329509

CAS#: 1008510-37-9 (free base)

Description: Razuprotafib, also known as AKB-9778, is a protein tyrosine phosphatase ß (HPTPß) inhibitor. AKB-9778 is a known VE-PTP inhibitor that can effectively interact with the active site of VE-PTP to inhibit the activity of VE-PTP.. AKB-9778 may function through reducing serum angiopoietin 2 level and regulating EC viability. AKB-9778 Improved Antitumor Activity and Diminishes the Toxicity of Interleukin 2 (IL-2) Administration. AKB-9778 significantly lowered systolic and diastolic blood pressure.

Chemical Structure

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Razuprotafib
CAS# 1008510-37-9 (free base)
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 329509
Name: Razuprotafib
CAS#: 1008510-37-9 (free base)
Chemical Formula: C26H26N4O6S3
Exact Mass: 586.10
Molecular Weight: 586.696
Elemental Analysis: C, 53.23; H, 4.47; N, 9.55; O, 16.36; S, 16.39

Price and Availability

Size Price Availability Quantity
5mg USD 150 Ready to ship
10mg USD 250 Ready to ship
25mg USD 450 Ready to ship
50mg USD 750 Ready to ship
100mg USD 1250 Ready to ship
200mg USD 1950 Ready to ship
500mg USD 3650 Ready to Ship
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Related CAS #: 1809275-69-1 (sodium)   1008510-37-9 (free base)  

Synonym: Razuprotafib; AKB-9778; AKB 9778; AKB9778;

IUPAC/Chemical Name: N-(4-{(2S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-phenylpropanamido}-2-[2-(thiophen-2-yl)-1,3-thiazol-4-yl]ethyl}phenyl)sulfamic acid

InChi Key: KWJDHELCGJFUHW-SFTDATJTSA-N

InChi Code: InChI=1S/C26H26N4O6S3/c1-36-26(32)29-21(15-17-6-3-2-4-7-17)24(31)27-20(22-16-38-25(28-22)23-8-5-13-37-23)14-18-9-11-19(12-10-18)30-39(33,34)35/h2-13,16,20-21,30H,14-15H2,1H3,(H,27,31)(H,29,32)(H,33,34,35)/t20-,21-/m0/s1

SMILES Code: O=S(O)(NC1=CC=C(C[C@H](NC([C@@H](NC(OC)=O)CC2=CC=CC=C2)=O)C3=CSC(C4=CC=CS4)=N3)C=C1)=O

Appearance: Solid powder

Purity: >98% (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 (Note: this product is less stable in acidic buffer, it is recommend to used basic buffer).

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

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:

Biological target: Razuprotafib (AKB-9778) is a potent and selective inhibitor of the catalytic activity of VE-PTP (vascular endothelial protein tyrosine phosphatase) with an IC50of 17 pM.
In vitro activity: AKB-9778 was further evaluated for whether itself affected the functions of immune cells and the viability on endothelial cells and tumor cells in vitro. In the classic 51Cr release assay, there was no apparent impact on splenocyte cytotoxicity, ranging from 10nM to 10μM (Supplementary Fig. S2). Furthermore, the capacities of tumor cell growth were not inhibited by treatment of AKB (AKB9778), indicating AKB didn’t act on tumor cells directly (Supplementary Fig. S3). To address the effect of AKB-9778 on endothelium, a common assay of angiogenesis, in which endothelial cells (ECs) are placed in a matrix of basement membrane proteins to assess their ability to form tube-like structures with neighboring cells was utilized. Specifically, we evaluated EC tube formation on matrigel in the presence of AKB-9778 at increasing concentrations. After four hours of culture on growth factor-reduced matrigel, tube formation was reduced in cells exposed to AKB-9778 at a dose of 1μg/ml and higher (Figure 4C). J Immunother. 2019 Sep; 42(7): 237–243. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088541/
In vivo activity: In order to investigate the potential of VE-PTP as a therapeutic target for vascular integrity, it was sought to determine the effects of administration of the VE-PTP inhibitor AKB-9778 (Aerpio Therapeutics; Cincinnati Ohio) either alone or in combination with IL-2, in a hepatic metastatic tumor model. Mice received 2X105 luciferase-labeled murine MC38 colorectal cancer cells via portal vein injection. Ten days after infusion/implantation (Day 0), they were randomly divided into 4 groups that received vehicle control (PBS), AKB-9778 alone 40mg/kg, twice a day for 5 days, rIL-2 600,000 IU per mouse (HDIL- 2), twice a day for 5 day, with or without combination of AKB-9778 (Figure 1A). AKB-9778 was administered 30 min prior to IL-2 according to the protocol others use (Cao M. and Yi T., unpublished data). Treatment with AKB-9778 alone had a negligible effect on tumor growth. To determine the effect of AKB-9778 on IL-2-induced vascular leakage, murine net lung weight as an indicator of edema was measured two hours following the last dose of IL-2 on Day 4 (Figure 1C). Administration of HDIL-2 dramatically increased the lung weight (p<0.001), which was significantly reduced with AKB 9778 (p<0.05, Figure 1C), demonstrating that the VE-PTP inhibitor, AKB 9778, protected mice against IL-2-induced VLS. Thus, AKB-9778 not only increased its efficacy of IL-2 treatment, but also helped relieve the side effects, slightly prolonging the resultant survival (Supplementary Fig. S1), approaching statistical significance (p = 0.07) J Immunother. 2019 Sep; 42(7): 237–243. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088541/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 100.0 170.44

Preparing Stock Solutions

The following data is based on the product molecular weight 586.70 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. Li G, Sachdev U, Peters K, Liang X, Lotze MT. The VE-PTP Inhibitor AKB-9778 Improves Antitumor Activity and Diminishes the Toxicity of Interleukin 2 (IL-2) Administration. J Immunother. 2019 Sep;42(7):237-243. doi: 10.1097/CJI.0000000000000290. PMID: 31348125; PMCID: PMC8088541. 2. Goel S, Gupta N, Walcott BP, Snuderl M, Kesler CT, Kirkpatrick ND, Heishi T, Huang Y, Martin JD, Ager E, Samuel R, Wang S, Yazbek J, Vakoc BJ, Peterson RT, Padera TP, Duda DG, Fukumura D, Jain RK. Effects of vascular-endothelial protein tyrosine phosphatase inhibition on breast cancer vasculature and metastatic progression. J Natl Cancer Inst. 2013 Aug 21;105(16):1188-201. doi: 10.1093/jnci/djt164. Epub 2013 Jul 30. Erratum in: J Natl Cancer Inst. 2013 Nov 20;105(22):1762. PMID: 23899555; PMCID: PMC3748004. 3. Shen J, Frye M, Lee BL, Reinardy JL, McClung JM, Ding K, Kojima M, Xia H, Seidel C, Lima e Silva R, Dong A, Hackett SF, Wang J, Howard BW, Vestweber D, Kontos CD, Peters KG, Campochiaro PA. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest. 2014 Oct;124(10):4564-76. doi: 10.1172/JCI74527. Epub 2014 Sep 2. PMID: 25180601; PMCID: PMC4191011.
In vitro protocol: 1. Li G, Sachdev U, Peters K, Liang X, Lotze MT. The VE-PTP Inhibitor AKB-9778 Improves Antitumor Activity and Diminishes the Toxicity of Interleukin 2 (IL-2) Administration. J Immunother. 2019 Sep;42(7):237-243. doi: 10.1097/CJI.0000000000000290. PMID: 31348125; PMCID: PMC8088541. 2. Goel S, Gupta N, Walcott BP, Snuderl M, Kesler CT, Kirkpatrick ND, Heishi T, Huang Y, Martin JD, Ager E, Samuel R, Wang S, Yazbek J, Vakoc BJ, Peterson RT, Padera TP, Duda DG, Fukumura D, Jain RK. Effects of vascular-endothelial protein tyrosine phosphatase inhibition on breast cancer vasculature and metastatic progression. J Natl Cancer Inst. 2013 Aug 21;105(16):1188-201. doi: 10.1093/jnci/djt164. Epub 2013 Jul 30. Erratum in: J Natl Cancer Inst. 2013 Nov 20;105(22):1762. PMID: 23899555; PMCID: PMC3748004.
In vivo protocol: 1. Li G, Sachdev U, Peters K, Liang X, Lotze MT. The VE-PTP Inhibitor AKB-9778 Improves Antitumor Activity and Diminishes the Toxicity of Interleukin 2 (IL-2) Administration. J Immunother. 2019 Sep;42(7):237-243. doi: 10.1097/CJI.0000000000000290. PMID: 31348125; PMCID: PMC8088541. 2. Shen J, Frye M, Lee BL, Reinardy JL, McClung JM, Ding K, Kojima M, Xia H, Seidel C, Lima e Silva R, Dong A, Hackett SF, Wang J, Howard BW, Vestweber D, Kontos CD, Peters KG, Campochiaro PA. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest. 2014 Oct;124(10):4564-76. doi: 10.1172/JCI74527. Epub 2014 Sep 2. PMID: 25180601; PMCID: PMC4191011.

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1: Ferro Desideri L, Traverso CE, Nicolò M. The emerging role of the Angiopoietin-Tie pathway as therapeutic target for treating retinal diseases. Expert Opin Ther Targets. 2022 Feb;26(2):145-154. doi: 10.1080/14728222.2022.2036121. Epub 2022 Feb 7. PMID: 35098845.


2: Schmaier AA, Pajares Hurtado GM, Manickas-Hill ZJ, Sack KD, Chen SM, Bhambhani V, Quadir J, Nath AK, Collier AY, Ngo D, Barouch DH, Shapiro NI, Gerszten RE, Yu XG; MGH COVID-19 Collection and Processing Team; Peters KG, Flaumenhaft R, Parikh SM. Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19. JCI Insight. 2021 Oct 22;6(20):e151527. doi: 10.1172/jci.insight.151527. PMID: 34506304; PMCID: PMC8564889.


3: Camilleri P, Soldo B, Buch A, Janusz J. Oxidative metabolism of razuprotafib (AKB-9778), a sulfamic acid phosphatase inhibitor, in human microsomes and recombinant human CYP2C8 enzyme. Xenobiotica. 2021 Oct;51(10):1110-1121. doi: 10.1080/00498254.2021.1969482. Epub 2021 Sep 3. PMID: 34477046.


4: Soldo BL, Camilleri P, Buch A, Janusz J. The in vivo disposition of subcutaneous injected 14C-razuprotafib (14C-AKB-9778), a sulphamic acid phosphatase inhibitor, in nonclinical species and human. Xenobiotica. 2021 Oct;51(10):1132-1145. doi: 10.1080/00498254.2021.1972358. Epub 2021 Sep 1. PMID: 34420473.


5: Schmaier AA, Hurtado GP, Manickas-Hill ZJ, Sack KD, Chen SM, Bhambhani V, Quadir J, Nath AK, Collier AY, Ngo D, Barouch DH, Gerszten RE, Yu XG; MGH COVID-19 Collection and Processing Team; Peters K, Flaumenhaft R, Parikh SM. Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19. medRxiv [Preprint]. 2021 May 17:2021.05.13.21257070. doi: 10.1101/2021.05.13.21257070. Update in: JCI Insight. 2021 Sep 10;: PMID: 34031665; PMCID: PMC8142666.


6: Justo AFO, Afonso PPL. The role of vascular endothelial protein tyrosine phosphatase on nitric oxide synthase function in diabetes: from molecular biology to the clinic. J Cell Commun Signal. 2021 Sep;15(3):467-471. doi: 10.1007/s12079-021-00611-9. Epub 2021 Mar 8. PMID: 33683570; PMCID: PMC8222474.


7: Li G, Nottebaum AF, Brigell M, Navarro ID, Ipe U, Mishra S, Gomez-Caraballo M, Schmitt H, Soldo B, Pakola S, Withers B, Peters KG, Vestweber D, Stamer WD. A Small Molecule Inhibitor of VE-PTP Activates Tie2 in Schlemm's Canal Increasing Outflow Facility and Reducing Intraocular Pressure. Invest Ophthalmol Vis Sci. 2020 Dec 1;61(14):12. doi: 10.1167/iovs.61.14.12. PMID: 33315051; PMCID: PMC7735951.


8: Siragusa M, Oliveira Justo AF, Malacarne PF, Strano A, Buch A, Withers B, Peters KG, Fleming I. VE-PTP inhibition elicits eNOS phosphorylation to blunt endothelial dysfunction and hypertension in diabetes. Cardiovasc Res. 2021 May 25;117(6):1546-1556. doi: 10.1093/cvr/cvaa213. PMID: 32653904.


9: Custo Greig E, Brigell M, Cao F, Levine ES, Peters K, Moult EM, Fujimoto JG, Waheed NK. Macular and Peripapillary Optical Coherence Tomography Angiography Metrics Predict Progression in Diabetic Retinopathy: A Sub-analysis of TIME-2b Study Data. Am J Ophthalmol. 2020 Nov;219:66-76. doi: 10.1016/j.ajo.2020.06.009. Epub 2020 Jun 20. PMID: 32574773.


10: Hussain RM, Neiweem AE, Kansara V, Harris A, Ciulla TA. Tie-2/Angiopoietin pathway modulation as a therapeutic strategy for retinal disease. Expert Opin Investig Drugs. 2019 Oct;28(10):861-869. doi: 10.1080/13543784.2019.1667333. Epub 2019 Sep 26. PMID: 31513439.


11: Drexler HCA, Vockel M, Polaschegg C, Frye M, Peters K, Vestweber D. Vascular Endothelial Receptor Tyrosine Phosphatase: Identification of Novel Substrates Related to Junctions and a Ternary Complex with EPHB4 and TIE2. Mol Cell Proteomics. 2019 Oct;18(10):2058-2077. doi: 10.1074/mcp.RA119.001716. Epub 2019 Aug 19. PMID: 31427368; PMCID: PMC6773558.


12: Li G, Sachdev U, Peters K, Liang X, Lotze MT. The VE-PTP Inhibitor AKB-9778 Improves Antitumor Activity and Diminishes the Toxicity of Interleukin 2 (IL-2) Administration. J Immunother. 2019 Sep;42(7):237-243. doi: 10.1097/CJI.0000000000000290. PMID: 31348125; PMCID: PMC8088541.


13: Liu WS, Wang RR, Sun YZ, Li WY, Li HL, Liu CL, Ma Y, Wang RL. Exploring the effect of inhibitor AKB-9778 on VE-PTP by molecular docking and molecular dynamics simulation. J Cell Biochem. 2019 Oct;120(10):17015-17029. doi: 10.1002/jcb.28963. Epub 2019 May 24. PMID: 31125141.


14: Fouli GE, Gnudi L. The Future: Experimental Therapies for Renal Disease in Diabetes. Nephron. 2019;143(1):3-7. doi: 10.1159/000492825. Epub 2018 Sep 26. PMID: 30257247.


15: Campochiaro PA, Peters KG. Targeting Tie2 for Treatment of Diabetic Retinopathy and Diabetic Macular Edema. Curr Diab Rep. 2016 Dec;16(12):126. doi: 10.1007/s11892-016-0816-5. PMID: 27778249.


16: Campochiaro PA, Khanani A, Singer M, Patel S, Boyer D, Dugel P, Kherani S, Withers B, Gambino L, Peters K, Brigell M; TIME-2 Study Group. Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression. Ophthalmology. 2016 Aug;123(8):1722-1730. doi: 10.1016/j.ophtha.2016.04.025. Epub 2016 May 26. PMID: 27236272.


17: Frye M, Dierkes M, Küppers V, Vockel M, Tomm J, Zeuschner D, Rossaint J, Zarbock A, Koh GY, Peters K, Nottebaum AF, Vestweber D. Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE- cadherin. J Exp Med. 2015 Dec 14;212(13):2267-87. doi: 10.1084/jem.20150718. Epub 2015 Dec 7. PMID: 26642851; PMCID: PMC4689167.


18: Campochiaro PA, Sophie R, Tolentino M, Miller DM, Browning D, Boyer DS, Heier JS, Gambino L, Withers B, Brigell M, Peters K. Treatment of diabetic macular edema with an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates Tie2. Ophthalmology. 2015 Mar;122(3):545-54. doi: 10.1016/j.ophtha.2014.09.023. Epub 2014 Nov 12. PMID: 25439435.


19: Shen J, Frye M, Lee BL, Reinardy JL, McClung JM, Ding K, Kojima M, Xia H, Seidel C, Lima e Silva R, Dong A, Hackett SF, Wang J, Howard BW, Vestweber D, Kontos CD, Peters KG, Campochiaro PA. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest. 2014 Oct;124(10):4564-76. doi: 10.1172/JCI74527. Epub 2014 Sep 2. PMID: 25180601; PMCID: PMC4191011.


20: Goel S, Gupta N, Walcott BP, Snuderl M, Kesler CT, Kirkpatrick ND, Heishi T, Huang Y, Martin JD, Ager E, Samuel R, Wang S, Yazbek J, Vakoc BJ, Peterson RT, Padera TP, Duda DG, Fukumura D, Jain RK. Effects of vascular-endothelial protein tyrosine phosphatase inhibition on breast cancer vasculature and metastatic progression. J Natl Cancer Inst. 2013 Aug 21;105(16):1188-201. doi: 10.1093/jnci/djt164. Epub 2013 Jul 30. Erratum in: J Natl Cancer Inst. 2013 Nov 20;105(22):1762. PMID: 23899555; PMCID: PMC3748004.