Afuresertib free base| CAS#1047644-62-1 | AKT inhibitor

MedKoo Cat#: 591336 | Name: Afuresertib free base

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Description:

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

Afuresertib, also known as GSK-2110183 or GSK-2110183C, is an orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) with potential antineoplastic activity. Afuresertib binds to and inhibits the activity of Akt, which may result in inhibition of the PI3K/Akt signaling pathway and tumor cell proliferation and the induction of tumor cell apoptosis. Activation of the PI3K/Akt signaling pathway is frequently associated with tumorigenesis

Chemical Structure

Afuresertib free base

CAS#1047644-62-1 (free base)

Theoretical Analysis

MedKoo Cat#: 591336

Name: Afuresertib free base

CAS#: 1047644-62-1 (free base)

Chemical Formula: C18H17Cl2FN4OS

Exact Mass: 426.0784

Molecular Weight: 427.32

Elemental Analysis: C, 50.59; H, 4.01; Cl, 16.59; F, 4.45; N, 13.11; O, 3.74; S, 7.50

Price and Availability

Size	Price	Availability	Quantity
10mg	USD 350.00	2 Weeks
100mg	USD 1,250.00	2 Weeks

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Related CAS #

1047644-62-1 (free base) 1047645-82-8 (HCl) 1047634-63-8 (Afuresertib-F free base) 2070009-64-0 (Afuresertib-F HCl)

Synonym

GSK2110183; GSK 2110183; GSK-2110183; GSK2110183C; GSK 2110183C; GSK2110183C; Afuresertib free base;

IUPAC/Chemical Name

2-Thiophenecarboxamide, N-((1S)-2-amino-1-((3-fluorophenyl)methyl)ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-

InChi Key

AFJRDFWMXUECEW-LBPRGKRZSA-N

InChi Code

InChI=1S/C18H17Cl2FN4OS/c1-25-16(14(19)9-23-25)13-7-15(27-17(13)20)18(26)24-12(8-22)6-10-3-2-4-11(21)5-10/h2-5,7,9,12H,6,8,22H2,1H3,(H,24,26)/t12-/m0/s1

SMILES Code

O=C(C1=CC(C2=C(Cl)C=NN2C)=C(Cl)S1)N[C@@H](CC3=CC=CC(F)=C3)CN

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

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

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Product Data

Product Data

Instruction

View handling instruction

Biological target:

Afuresertib (GSK2110183) is a ATP-competitive pan-Akt kinase inhibitor with Kis of 0.08/2/2.6 nM for Akt1/Akt2/Akt3, respectively.

In vitro activity:

This study found that afuresertib enhanced the phosphorylation of Akt at Thr308 and Ser473, which is consistent with that observed using other catalytic, ATP-competitive Akt inhibitors, including GDC-0068. Results of gene expression profiling performed in this study showed that afuresertib significantly suppresses oncogenic gene expression related to serum response, E2F1, MYC, mTOR, as well as Akt. This result suggests that afuresertib-induced hyperphosphorylation does not activate of Akt-mediated signaling. Afuresertib increased the expression of gene sets associated with inositol phosphate and/or amino acid metabolisms, including branched chain amino acids (BCAAs) and tryptophan metabolism, suggesting that these metabolic pathways are alternatively used to supply cellular energy after Akt inhibition in MPM cells. Therefore, it would be interesting to examine whether inhibition of inositol phosphate and/or BCAA metabolic pathways enhances afuresertib-induced suppression in MPM cells. Reference: Cancer Med. 2017 Nov; 6(11): 2646–2659. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673922/

In vivo activity:

Next, the in vivo efficacy of curcumin and afuresertib for the treatment of AML was evaluated. NOD/SCID mice were intravenously injected with 1×106 ML-2 cells. Drug treatment began 15 days after injection and continued every other day for 16 days. After treatment, peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) were isolated and evaluated for human hematopoietic (hCD45) chimerism via flow cytometry (Fig. 4). Compared with the control group (VEH), the mice treated with curcumin (CCM) or afuresertib (AFU) either alone or in combination (CCM+AFU) had fewer human CD45+ cells in the bone marrow and peripheral blood. Moreover, combination drug therapy was more effective than single drug therapy in reducing the chimerism of hCD45 (Fig. 4). These results indicated that curcumin and afuresertib synergistically suppressed the engraftment of AML cells. Reference: Oncol Rep. 2021 Apr; 45(4): 11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877002/

	Solvent	mg/mL	mM
Solubility
	DMSO	62.5	146.26
	Ethanol	85.0	198.91

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 427.32 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.

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. Wu JH, Limmer AL, Narayanan D, Doan HQ, Simonette RA, Rady PL, Tyring SK. The novel AKT inhibitor Afuresertib suppresses human Merkel cell carcinoma MKL-1 cell growth. Clin Exp Dermatol. 2021 Jun 11. doi: 10.1111/ced.14798. Epub ahead of print. PMID: 34115902. 2. Yamaji M, Ota A, Wahiduzzaman M, Karnan S, Hyodo T, Konishi H, Tsuzuki S, Hosokawa Y, Haniuda M. Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27. PMID: 28960945; PMCID: PMC5673922. 3. Zhou H, Ning Y, Zeng G, Zhou C, Ding X. Curcumin promotes cell cycle arrest and apoptosis of acute myeloid leukemia cells by inactivating AKT. Oncol Rep. 2021 Apr;45(4):11. doi: 10.3892/or.2021.7962. Epub 2021 Mar 2. PMID: 33649826; PMCID: PMC7877002.

In vitro protocol:

In vivo protocol:

1. Zhou H, Ning Y, Zeng G, Zhou C, Ding X. Curcumin promotes cell cycle arrest and apoptosis of acute myeloid leukemia cells by inactivating AKT. Oncol Rep. 2021 Apr;45(4):11. doi: 10.3892/or.2021.7962. Epub 2021 Mar 2. PMID: 33649826; PMCID: PMC7877002.

1: Uko NE, Güner OF, Matesic DF, Bowen JP. Akt Pathway Inhibitors. Curr Top Med Chem. 2020;20(10):883-900. doi: 10.2174/1568026620666200224101808. PMID: 32091335. 2: Min B, Wang Y, Liang F, Wang CX, Wang F, Yang Z. The Protective Mechanism of Afuresertib against Esophageal Cancer. Dis Markers. 2022 Jul 14;2022:1832241. doi: 10.1155/2022/1832241. PMID: 35872696; PMCID: PMC9303141. 3: Cho H, Abshire ET, Popp MW, Pröschel C, Schwartz JL, Yeo GW, Maquat LE. AKT constitutes a signal-promoted alternative exon-junction complex that regulates nonsense-mediated mRNA decay. Mol Cell. 2022 Aug 4;82(15):2779-2796.e10. doi: 10.1016/j.molcel.2022.05.013. Epub 2022 Jun 7. PMID: 35675814; PMCID: PMC9357146. 4: Zhou H, Ning Y, Zeng G, Zhou C, Ding X. Curcumin promotes cell cycle arrest and apoptosis of acute myeloid leukemia cells by inactivating AKT. Oncol Rep. 2021 Apr;45(4):11. doi: 10.3892/or.2021.7962. Epub 2021 Mar 2. PMID: 33649826; PMCID: PMC7877002. 5: Wu JH, Limmer AL, Narayanan D, Doan HQ, Simonette RA, Rady PL, Tyring SK. The novel AKT inhibitor afuresertib suppresses human Merkel cell carcinoma MKL-1 cell growth. Clin Exp Dermatol. 2021 Dec;46(8):1551-1554. doi: 10.1111/ced.14798. Epub 2021 Aug 26. PMID: 34115902. 6: Yamaji M, Ota A, Wahiduzzaman M, Karnan S, Hyodo T, Konishi H, Tsuzuki S, Hosokawa Y, Haniuda M. Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27. PMID: 28960945; PMCID: PMC5673922. 7: Blagden SP, Hamilton AL, Mileshkin L, Wong S, Michael A, Hall M, Goh JC, Lisyanskaya AS, DeSilvio M, Frangou E, Stronach EA, Gopalakrishna P, Meniawy TM, Gabra H. Phase IB Dose Escalation and Expansion Study of AKT Inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-resistant Ovarian Cancer. Clin Cancer Res. 2019 Mar 1;25(5):1472-1478. doi: 10.1158/1078-0432.CCR-18-2277. Epub 2018 Dec 18. PMID: 30563934. 8: Arceci RJ, Allen CE, Dunkel IJ, Jacobsen E, Whitlock J, Vassallo R, Morris SR, Portnoy A, Reedy BA, Smith DA, Noble R, Murnane A, Cornfeld M, Rodriguez- Galindo C, Heaney ML, McClain K, Vaiselbuh S. A phase IIa study of afuresertib, an oral pan-AKT inhibitor, in patients with Langerhans cell histiocytosis. Pediatr Blood Cancer. 2017 May;64(5). doi: 10.1002/pbc.26325. Epub 2016 Nov 2. PMID: 27804235. 9: Spencer A, Yoon SS, Harrison SJ, Morris SR, Smith DA, Brigandi RA, Gauvin J, Kumar R, Opalinska JB, Chen C. The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood. 2014 Oct 2;124(14):2190-5. doi: 10.1182/blood-2014-03-559963. Epub 2014 Jul 29. PMID: 25075128; PMCID: PMC4229853. 10: Chen CI, Paul H, Le LW, Wei EN, Snitzler S, Wang T, Levina O, Kakar S, Lau A, Queau M, Johnston JB, Smith DA, Trudel S. A phase 2 study of ofatumumab (Arzerra®) in combination with a pan-AKT inhibitor (afuresertib) in previously treated patients with chronic lymphocytic leukemia (CLL). Leuk Lymphoma. 2019 Jan;60(1):92-100. doi: 10.1080/10428194.2018.1468892. Epub 2018 Jun 19. PMID: 29916761. 11: Tolcher AW, Patnaik A, Papadopoulos KP, Rasco DW, Becerra CR, Allred AJ, Orford K, Aktan G, Ferron-Brady G, Ibrahim N, Gauvin J, Motwani M, Cornfeld M. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother Pharmacol. 2015 Jan;75(1):183-9. doi: 10.1007/s00280-014-2615-5. Epub 2014 Nov 25. PMID: 25417902. 12: Naymagon L, Abdul-Hay M. Novel agents in the treatment of multiple myeloma: a review about the future. J Hematol Oncol. 2016 Jun 30;9(1):52. doi: 10.1186/s13045-016-0282-1. PMID: 27363832; PMCID: PMC4929712. 13: Kong W, Zhu L, Li T, Chen J, Fan B, Ji W, Zhang C, Cai X, Hu C, Sun X, Cao P. Azeliragon inhibits PAK1 and enhances the therapeutic efficacy of AKT inhibitors in pancreatic cancer. Eur J Pharmacol. 2023 Jun 5;948:175703. doi: 10.1016/j.ejphar.2023.175703. Epub 2023 Apr 5. PMID: 37028543. 14: Wang J, Xu X, Wang T, Guo Q, Dai X, Guo H, Zhang W, Cheng S, Chen X, Ding L. Ceritinib increases sensitivity of AKT inhibitors to gastric cancer. Eur J Pharmacol. 2021 Apr 5;896:173879. doi: 10.1016/j.ejphar.2021.173879. Epub 2021 Jan 28. PMID: 33515539. 15: Wang B, Jiang L, Guo H, Sun Q, Wang Y, Xie E, Xia Q. Screening of PI3K-Akt- targeting Drugs for Silkworm against Bombyx mori Nucleopolyhedrovirus. Molecules. 2019 Apr 1;24(7):1260. doi: 10.3390/molecules24071260. PMID: 30939726; PMCID: PMC6480691. 16: Keane NA, Glavey SV, Krawczyk J, O'Dwyer M. AKT as a therapeutic target in multiple myeloma. Expert Opin Ther Targets. 2014 Aug;18(8):897-915. doi: 10.1517/14728222.2014.924507. Epub 2014 Jun 6. PMID: 24905897. 17: Chen R, Ning Y, Zeng G, Zhou H, Zhou L, Xiao P, Li Z, Zhou J. The miR-193a-5p/NCX2/AKT axis promotes invasion and metastasis of osteosarcoma. J Cancer. 2021 Aug 8;12(19):5903-5913. doi: 10.7150/jca.60969. PMID: 34476004; PMCID: PMC8408106. 18: Karnan S, Hanamura I, Ota A, Takasugi S, Nakamura A, Takahashi M, Uchino K, Murakami S, Wahiduzzaman M, Quang Vu L, Rahman ML, Hasan MN, Hyodo T, Konishi H, Tsuzuki S, Yoshikawa K, Suzuki S, Ueda R, Ejiri M, Hosokawa Y, Takami A. CD52 is a novel target for the treatment of FLT3-ITD-mutated myeloid leukemia. Cell Death Discov. 2021 May 25;7(1):121. doi: 10.1038/s41420-021-00446-8. PMID: 34035227; PMCID: PMC8149417. 19: Wiechmann S, Ruprecht B, Siekmann T, Zheng R, Frejno M, Kunold E, Bajaj T, Zolg DP, Sieber SA, Gassen NC, Kuster B. Chemical Phosphoproteomics Sheds New Light on the Targets and Modes of Action of AKT Inhibitors. ACS Chem Biol. 2021 Apr 16;16(4):631-641. doi: 10.1021/acschembio.0c00872. Epub 2021 Mar 23. PMID: 33755436. 20: Ni H, Shirazi F, Baladandayuthapani V, Lin H, Kuiatse I, Wang H, Jones RJ, Berkova Z, Hitoshi Y, Ansell SM, Treon SP, Thomas SK, Lee HC, Wang Z, Davis RE, Orlowski RZ. Targeting Myddosome Signaling in Waldenström's Macroglobulinemia with the Interleukin-1 Receptor-Associated Kinase 1/4 Inhibitor R191. Clin Cancer Res. 2018 Dec 15;24(24):6408-6420. doi: 10.1158/1078-0432.CCR-17-3265. Epub 2018 Aug 20. PMID: 30126942; PMCID: PMC6295253.