GSK864 | GSK-864 | CAS#1816331-66-4 | IDH1 inhibitor

MedKoo Cat#: 407369 | Name: GSK864

Description:

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

GSK864 is a potent and selective inhibitor of mutant IDH1. GSK864 inhibits IDH1 mutants R132C/R132H/R132G with IC50 values of 9/15/17 nM, respectively, and is moderately selective over wild-type IDH1 and IDH2 mutants/wild-type. Treatment of R132C IDH1 mutant HT-1080 cells for 24 hours with GSK864 results in a dose-dependent reduction of 2-hydroxyglutarate (2-HG), which is not observed with GSK990, a structurally similar compound which is inactive as an IDH1 inhibitor. GSK864 has been shown to be selective in vitro for IDH1 over other classes of proteins (7TMs, ion channels, kinases) and chemoproteomic studies with GSK321, an analog of GSK864, confirm selective binding of IDH1 by this chemical series. GSK864 has a pharmacokinetic profile suitable for in vivo studies.

Chemical Structure

GSK864

CAS#1816331-66-4

Theoretical Analysis

MedKoo Cat#: 407369

Name: GSK864

CAS#: 1816331-66-4

Chemical Formula: C30H31FN6O4

Exact Mass: 558.2391

Molecular Weight: 558.61

Elemental Analysis: C, 64.50; H, 5.59; F, 3.40; N, 15.04; O, 11.46

Price and Availability

Size	Price	Availability
10mg	USD 650.00	2 Weeks
100mg	USD 1,950.00	2 Weeks
1g	USD 5,650.00	2 Weeks
2g	USD 8,950.00	2 Weeks

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Related CAS #

No Data

Synonym

GSK864; GSK-864; GSK 864.

IUPAC/Chemical Name

(S)-1-(4-fluorobenzyl)-N3-(4-methoxy-3,5-dimethylphenyl)-7-methyl-5-(1H-pyrrole-2-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3,7-dicarboxamide

InChi Key

DUCNNEYLFOQFSW-PMERELPUSA-N

InChi Code

InChI=1S/C30H31FN6O4/c1-17-12-21(13-18(2)25(17)41-4)34-27(38)24-22-15-36(28(39)23-6-5-11-33-23)16-30(3,29(32)40)26(22)37(35-24)14-19-7-9-20(31)10-8-19/h5-13,33H,14-16H2,1-4H3,(H2,32,40)(H,34,38)/t30-/m0/s1

SMILES Code

O=C(C1=NN(CC2=CC=C(F)C=C2)C3=C1CN(C(C4=CC=CN4)=O)C[C@]3(C)C(N)=O)NC5=CC(C)=C(OC)C(C)=C5

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

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

GSK864 is an isocitrate dehydrogenase 1 (IDH1) mutant inhibitor; inhibits IDH1 mutants R132C, R132H, and R132G with IC50 values of 8.8, 15.2 and 16.6 nM.

In vitro activity:

Indeed, GSK864 attenuated the proliferation of both fibrosarcoma cells and normal fibroblasts with a similar trend (Figure 5B). Despite their different proliferation rates, GSK864 significantly reduced the proliferation of fibrosarcoma cells and normal fibroblasts at doses of 0.8, 1.6 and 2 μmol, relative to control and at doses of 0.2 and 0.4 μmol (Figure 5B). These findings suggest that GSK864 not only attenuated the proliferation of IDH1 mutant cancer cells, but also fibroblasts such as those found in cancer stroma. Thus, GSK864 attenuation of vascular-endothelial tube formation (Figure 3), reversable by IDH mutant 2HG to which GSK864 inhibits, may represent a novel me-chanism by which GSK864 or other small molecules may be harnessed to target cancer stromal cells. Reference: Am J Cancer Res. 2019 Jan 1;9(1):122-133. https://pubmed.ncbi.nlm.nih.gov/30755816/

In vivo activity:

IDH1 WT or mutant AML patient BM cells were transplanted into sublethally irradiated NSG mice (Supplementary Fig. 4a), and comparable levels of AML engraftment were observed in BM aspirates 3 weeks after transplantation, and prior to treatment with either vehicle or 150 mg/kg GSK864. Following treatment this study observed a decrease in 2HG in IDH1-mutant AML cells of GSK321 treated mice (Supplementary Fig. 3f). After treatment with GSK864, this study observed a significant decrease in the percentage of blast cells (SSClow CD45low/+) and a relative increase in mature lymphoid and granulocytic/monocytic cells (Supplementary Fig. 4c). Reference: Nat Chem Biol. 2015 Nov;11(11):878-86. https://pubmed.ncbi.nlm.nih.gov/26436839/

	Solvent	mg/mL	mM
Solubility
	DMF	20.0	35.80
	DMSO	60.0	107.41
	Ethanol	20.0	35.80
	Ethanol:PBS (pH 7.2) (1:1)	0.5	0.90

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 558.61 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. Mao MJ, Leonardi DE. Vascular-endothelial response to IDH1 mutant fibrosarcoma secretome and metabolite: implications on cancer microenvironment. Am J Cancer Res. 2019 Jan 1;9(1):122-133. PMID: 30755816; PMCID: PMC6356916. 2. Okoye-Okafor UC, Bartholdy B, Cartier J, Gao EN, Pietrak B, Rendina AR, Rominger C, Quinn C, Smallwood A, Wiggall KJ, Reif AJ, Schmidt SJ, Qi H, Zhao H, Joberty G, Faelth-Savitski M, Bantscheff M, Drewes G, Duraiswami C, Brady P, Groy A, Narayanagari SR, Antony-Debre I, Mitchell K, Wang HR, Kao YR, Christopeit M, Carvajal L, Barreyro L, Paietta E, Makishima H, Will B, Concha N, Adams ND, Schwartz B, McCabe MT, Maciejewski J, Verma A, Steidl U. New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. Nat Chem Biol. 2015 Nov;11(11):878-86. doi: 10.1038/nchembio.1930. Epub 2015 Oct 5. PMID: 26436839; PMCID: PMC5155016.

In vitro protocol:

In vivo protocol:

1. Okoye-Okafor UC, Bartholdy B, Cartier J, Gao EN, Pietrak B, Rendina AR, Rominger C, Quinn C, Smallwood A, Wiggall KJ, Reif AJ, Schmidt SJ, Qi H, Zhao H, Joberty G, Faelth-Savitski M, Bantscheff M, Drewes G, Duraiswami C, Brady P, Groy A, Narayanagari SR, Antony-Debre I, Mitchell K, Wang HR, Kao YR, Christopeit M, Carvajal L, Barreyro L, Paietta E, Makishima H, Will B, Concha N, Adams ND, Schwartz B, McCabe MT, Maciejewski J, Verma A, Steidl U. New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. Nat Chem Biol. 2015 Nov;11(11):878-86. doi: 10.1038/nchembio.1930. Epub 2015 Oct 5. PMID: 26436839; PMCID: PMC5155016.

1. Mao MJ, Leonardi DE. Vascular-endothelial response to IDH1 mutant fibrosarcoma secretome and metabolite: implications on cancer microenvironment. Am J Cancer Res. 2019 Jan 1;9(1):122-133. PMID: 30755816; PMCID: PMC6356916. 2. Barghout SH, Mann MK, Aman A, Yu Y, Alteen MG, Schimmer AD, Schapira M, Arrowsmith CH, Barsyte-Lovejoy D. Combinatorial Anticancer Drug Screen Identifies Off-Target Effects of Epigenetic Chemical Probes. ACS Chem Biol. 2022 Oct 21;17(10):2801-2816. doi: 10.1021/acschembio.2c00451. Epub 2022 Sep 9. PMID: 36084291.