Afuresertib HCl
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MedKoo CAT#: 205478

CAS#: 1047645-82-8 (HCl)

Description: Afuresertib, also known as GSK2110183, is an orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) with potential antineoplastic activity. Akt inhibitor GSK2110183 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 and dysregulated PI3K/Akt signaling may contribute to tumor resistance to a variety of antineoplastic agents.


Chemical Structure

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Afuresertib HCl
CAS# 1047645-82-8 (HCl)

Theoretical Analysis

MedKoo Cat#: 205478
Name: Afuresertib HCl
CAS#: 1047645-82-8 (HCl)
Chemical Formula: C18H18Cl3FN4OS
Exact Mass:
Molecular Weight: 463.78
Elemental Analysis: C, 46.62; H, 3.91; Cl, 22.93; F, 4.10; N, 12.08; O, 3.45; S, 6.91

Price and Availability

Size Price Availability Quantity
25.0mg USD 150.0 Same day
50.0mg USD 250.0 Same day
100.0mg USD 450.0 Same day
200.0mg USD 650.0 Same day
500.0mg USD 1450.0 Same day
1.0g USD 2450.0 Same day
2.0g USD 3850.0 2 Weeks
5.0g USD 5450.0 2 weeks
10.0g USD 7950.0 2 weeks
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Related CAS #: 1047634-63-8 (free base)   1047645-82-8 (HCl)   1047644-62-1 (free base)   2070009-64-0 (HCl)    

Synonym: GSK2110183; GSK 2110183; GSK-2110183; GSK2110183B; GSK 2110183B; GSK2110183B; Afuresertib; Afuresertib HCl; Afuresertib hydrochloride.

IUPAC/Chemical Name: N-((S)-1-amino-3-(3-fluorophenyl)propan-2-yl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)thiophene-2-carboxamide hydrochloride

InChi Key: YFQJOPFTGMHYNV-YDALLXLXSA-N

InChi Code: InChI=1S/C18H17Cl2FN4OS.ClH/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);1H/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.[H]Cl

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, not in water

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

Biological target: Afuresertib hydrochloride (GSK 2110183 hydrochloride) is an 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/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 65.0 140.15
DMF 50.0 107.81
Ethanol 50.0 107.81
Ethanol:PBS (pH 7.2) (1:1) 0.5 1.08

Preparing Stock Solutions

The following data is based on the product molecular weight 463.78 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. 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. 2. 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. 3. 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.
In vitro 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.
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.

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1: 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 Aug 20. doi: 10.1158/1078-0432.CCR-17-3265. [Epub ahead of print] PubMed PMID: 30126942.

2: Kinoshita S, Ri M, Kanamori T, Aoki S, Yoshida T, Narita T, Totani H, Ito A, Kusumoto S, Ishida T, Komatsu H, Iida S. Potent antitumor effect of combination therapy with sub-optimal doses of Akt inhibitors and pomalidomide plus dexamethasone in multiple myeloma. Oncol Lett. 2018 Jun;15(6):9450-9456. doi: 10.3892/ol.2018.8501. Epub 2018 Apr 16. PubMed PMID: 29928335; PubMed Central PMCID: PMC6004690.

3: 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. 2018 Jun 19:1-9. doi: 10.1080/10428194.2018.1468892. [Epub ahead of print] PubMed PMID: 29916761.

4: 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. PubMed PMID: 28960945; PubMed Central PMCID: PMC5673922.

5: 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. PubMed PMID: 27804235.

6: 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. Review. PubMed PMID: 27363832; PubMed Central PMCID: PMC4929712.

7: 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. PubMed PMID: 25417902.

8: Leleu X. A key to the quest? Blood. 2014 Oct 2;124(14):2162-3. doi: 10.1182/blood-2014-08-593822. PubMed PMID: 25278563.

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. PubMed PMID: 25075128; PubMed Central PMCID: PMC4229853.

10: 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. Review. PubMed PMID: 24905897.



Additional Information

Related:
1047645-82-8 (Afuresertib HCl)
1047644-62-1 (Afuresertib free base).