AGI-5198 | IDH-C35 | CAS#1355326-35-0 | Mutant IDH1 Inhibitor

MedKoo Cat#: 406264 | Name: AGI-5198

Description:

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

AGI-5198, also know as IDH-C35, is the a very potent and selective mutant IDH1 inhibitor that was shown to potential anticancer activity. AGI-5198 shows good potency in the U87 R132H cell based assay and ~90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. AGI-5198 inhibits IDH1 R132H mutant and R132C mutant in vitro with IC50 ~0.07 μM and ~0.16 μM, respectively.

Chemical Structure

AGI-5198

CAS#1355326-35-0

Theoretical Analysis

MedKoo Cat#: 406264

Name: AGI-5198

CAS#: 1355326-35-0

Chemical Formula: C27H31FN4O2

Exact Mass: 462.2431

Molecular Weight: 462.56

Elemental Analysis: C, 70.11; H, 6.76; F, 4.11; N, 12.11; O, 6.92

Price and Availability

Size	Price	Availability
10mg	USD 90.00	Ready to ship
25mg	USD 150.00	Ready to ship
50mg	USD 215.00	Ready to ship
100mg	USD 350.00	Ready to ship
200mg	USD 615.00	Ready to ship
500mg	USD 1,250.00	Ready to ship

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Synonym

AGI5198; AGI-5198; AGI 5198; IDHC35; IDH-C35; IDH C35.

IUPAC/Chemical Name

N-cyclohexyl-2-(N-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetamido)-2-(o-tolyl)acetamide

InChi Key

FNYGWXSATBUBER-UHFFFAOYSA-N

InChi Code

InChI=1S/C27H31FN4O2/c1-19-9-6-7-14-24(19)26(27(34)30-22-11-4-3-5-12-22)32(23-13-8-10-21(28)17-23)25(33)18-31-16-15-29-20(31)2/h6-10,13-17,22,26H,3-5,11-12,18H2,1-2H3,(H,30,34)

SMILES Code

O=C(NC1CCCCC1)C(N(C2=CC=CC(F)=C2)C(CN3C=CN=C3C)=O)C4=CC=CC=C4C

Appearance

white to off-white 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

More Info

ML-309 , a Me-Too version of AGI-5198 is recently added in our website. Their chemical structures are compared side-by-side as the following:

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#SSC51129

View CoA: current batch, Lot#SSC51218

View CoA: current batch, Lot#BBC50727

QC Data

View QC data: current batch, Lot#BBC50727

View QC data: current batch, Lot#SSC51129

View QC data: current batch, Lot#SSC51218

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

AGI-5198 (IDH-C35) is a potent and selective mutant IDH1R132H inhibitor with an IC50 of 0.07 μM.

In vitro activity:

The activity of AGI-5198 in TS603 glioma cells with an endogenous heterozygous R132H-IDH1 mutation, the most common IDH mutation in glioma, was explored. TS603 cells were derived from a patient with anaplastic oligodendroglioma (WHO grade III) and harbor another pathognomomic lesion for this glioma subtype, namely co-deletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) (19) (Fig. 1C). Measurements of R-2HG concentrations in pellets of TS603 glioma cells demonstrated dose-dependent inhibition of the mutant IDH1 enzyme by AGI-5198 (Fig. 1D). When added to TS603 glioma cells growing in soft agar, AGI-5198 inhibited colony formation by 40 to 60% (Fig. 1E). AGI-5198 did not impair colony formation of two patient-derived glioma lines that express only the wild-type IDH1 allele (TS676 and TS516) (Fig. 1F), further supporting the selectivity of AGI-5198. Reference: Science. 2013 May 3;340(6132):626-30. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23558169/

In vivo activity:

The effects of orally administered AGI-5198 on the growth of human glioma xenografts were examined. When given daily to mice with established R132H-IDH1 glioma xenografts, AGI-5198 [450 mg per kg of weight (mg/kg) per os] caused 50 to 60% growth inhibition (Fig. 2A). Treatment was tolerated well with no signs of toxicity during 3 weeks of daily treatment (fig. S3). Tumors from AGI-5198– treated mice showed reduced staining with an antibody against the Ki-67 protein, a marker used for quantification of tumor cell proliferation in human brain tumors. In contrast, staining with an antibody against cleaved caspase-3 showed no differences between tumors from vehicle and AGI-5198–treated mice (fig. S4), suggesting that the growth-inhibitory effects of AGI-5198 were primarily due to impaired tumor cell proliferation rather than induction of apoptotic cell death. AGI-5198 did not affect the growth of IDH1 wild-type glioma xenografts (Fig. 2B). Reference: Science. 2013 May 3;340(6132):626-30. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23558169/

	Solvent	mg/mL	mM
Solubility
	DMSO	24.0	51.89
	Ethanol	14.0	30.27

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 462.56 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:

In vitro protocol:

1. Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, Tsoi J, Clark O, Oldrini B, Komisopoulou E, Kunii K, Pedraza A, Schalm S, Silverman L, Miller A, Wang F, Yang H, Chen Y, Kernytsky A, Rosenblum MK, Liu W, Biller SA, Su SM, Brennan CW, Chan TA, Graeber TG, Yen KE, Mellinghoff IK. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013 May 3;340(6132):626-30. doi: 10.1126/science.1236062. Epub 2013 Apr 4. PMID: 23558169; PMCID: PMC3985613.

In vivo protocol:

1: Chitneni SK, Reitman ZJ, Spicehandler R, Gooden DM, Yan H, Zalutsky MR. Synthesis and evaluation of radiolabeled AGI-5198 analogues as candidate radiotracers for imaging mutant IDH1 expression in tumors. Bioorg Med Chem Lett. 2018 Feb 15;28(4):694-699. doi: 10.1016/j.bmcl.2018.01.015. Epub 2018 Jan 12. PMID: 29366652; PMCID: PMC5817038. 2: Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, Tsoi J, Clark O, Oldrini B, Komisopoulou E, Kunii K, Pedraza A, Schalm S, Silverman L, Miller A, Wang F, Yang H, Chen Y, Kernytsky A, Rosenblum MK, Liu W, Biller SA, Su SM, Brennan CW, Chan TA, Graeber TG, Yen KE, Mellinghoff IK. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013 May 3;340(6132):626-30. doi: 10.1126/science.1236062. Epub 2013 Apr 4. PMID: 23558169; PMCID: PMC3985613. 3: Molenaar RJ, Botman D, Smits MA, Hira VV, van Lith SA, Stap J, Henneman P, Khurshed M, Lenting K, Mul AN, Dimitrakopoulou D, van Drunen CM, Hoebe RA, Radivoyevitch T, Wilmink JW, Maciejewski JP, Vandertop WP, Leenders WP, Bleeker FE, van Noorden CJ. Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198. Cancer Res. 2015 Nov 15;75(22):4790-802. doi: 10.1158/0008-5472.CAN-14-3603. Epub 2015 Sep 11. PMID: 26363012. 4: Carney SV, Banerjee K, Mujeeb A, Zhu B, Haase S, Varela ML, Kadiyala P, Tronrud CE, Zhu Z, Mukherji D, Gorla P, Sun Y, Tagett R, Núñez FJ, Luo M, Luo W, Ljungman M, Liu Y, Xia Z, Schwendeman A, Qin T, Sartor MA, Costello JF, Cahill DP, Lowenstein PR, Castro MG. Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance. Clin Cancer Res. 2023 May 1;29(9):1763-1782. doi: 10.1158/1078-0432.CCR-22-1896. PMID: 36692427; PMCID: PMC10159884. 5: Dang L, Su SM. Isocitrate Dehydrogenase Mutation and (R)-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Development. Annu Rev Biochem. 2017 Jun 20;86:305-331. doi: 10.1146/annurev-biochem-061516-044732. Epub 2017 Apr 3. PMID: 28375741. 6: Tiburcio PDB, Gillespie DL, Jensen RL, Huang LE. Extracellular glutamate and IDH1R132H inhibitor promote glioma growth by boosting redox potential. J Neurooncol. 2020 Feb;146(3):427-437. doi: 10.1007/s11060-019-03359-w. Epub 2020 Feb 4. PMID: 32020473; PMCID: PMC7440756. 7: Venneker S, Kruisselbrink AB, Baranski Z, Palubeckaite I, Briaire-de Bruijn IH, Oosting J, French PJ, Danen EHJ, Bovée JVMG. Beyond the Influence of IDH Mutations: Exploring Epigenetic Vulnerabilities in Chondrosarcoma. Cancers (Basel). 2020 Nov 30;12(12):3589. doi: 10.3390/cancers12123589. PMID: 33266275; PMCID: PMC7760027. 8: Kim J, DeBerardinis RJ. Cancer. Silencing a metabolic oncogene. Science. 2013 May 3;340(6132):558-9. doi: 10.1126/science.1238523. PMID: 23641103; PMCID: PMC4324171. 9: Cuyàs E, Fernández-Arroyo S, Corominas-Faja B, Rodríguez-Gallego E, Bosch- Barrera J, Martin-Castillo B, De Llorens R, Joven J, Menendez JA. Oncometabolic mutation IDH1 R132H confers a metformin-hypersensitive phenotype. Oncotarget. 2015 May 20;6(14):12279-96. doi: 10.18632/oncotarget.3733. PMID: 25980580; PMCID: PMC4494938. 10: Johannessen TA, Mukherjee J, Viswanath P, Ohba S, Ronen SM, Bjerkvig R, Pieper RO. Rapid Conversion of Mutant IDH1 from Driver to Passenger in a Model of Human Gliomagenesis. Mol Cancer Res. 2016 Oct;14(10):976-983. doi: 10.1158/1541-7786.MCR-16-0141. Epub 2016 Jul 18. PMID: 27430238; PMCID: PMC5065766. 11: Kim GH, Choi SY, Oh TI, Kan SY, Kang H, Lee S, Oh T, Ko HM, Lim JH. IDH1R132H Causes Resistance to HDAC Inhibitors by Increasing NANOG in Glioblastoma Cells. Int J Mol Sci. 2019 May 31;20(11):2679. doi: 10.3390/ijms20112679. PMID: 31151327; PMCID: PMC6600637. 12: Shi X, He BL, Ma AC, Guo Y, Chi Y, Man CH, Zhang W, Zhang Y, Wen Z, Cheng T, Leung AY. Functions of idh1 and its mutation in the regulation of developmental hematopoiesis in zebrafish. Blood. 2015 May 7;125(19):2974-84. doi: 10.1182/blood-2014-09-601187. Epub 2015 Mar 16. PMID: 25778530. 13: Zarei M, Lal S, Vaziri-Gohar A, O'Hayer K, Gunda V, Singh PK, Brody JR, Winter JM. RNA-Binding Protein HuR Regulates Both Mutant and Wild-Type IDH1 in IDH1-Mutated Cancer. Mol Cancer Res. 2019 Feb;17(2):508-520. doi: 10.1158/1541-7786.MCR-18-0557. Epub 2018 Sep 28. PMID: 30266754; PMCID: PMC6359963. 14: de Jong Y, Ingola M, Briaire-de Bruijn IH, Kruisselbrink AB, Venneker S, Palubeckaite I, Heijs BPAM, Cleton-Jansen AM, Haas RLM, Bovée JVMG. Radiotherapy resistance in chondrosarcoma cells; a possible correlation with alterations in cell cycle related genes. Clin Sarcoma Res. 2019 May 28;9:9. doi: 10.1186/s13569-019-0119-0. PMID: 31160965; PMCID: PMC6540537. 15: Peeters TH, Lenting K, Breukels V, van Lith SAM, van den Heuvel CNAM, Molenaar R, van Rooij A, Wevers R, Span PN, Heerschap A, Leenders WPJ. Isocitrate dehydrogenase 1-mutated cancers are sensitive to the green tea polyphenol epigallocatechin-3-gallate. Cancer Metab. 2019 May 20;7:4. doi: 10.1186/s40170-019-0198-7. PMID: 31139406; PMCID: PMC6526618. 16: Park J, Na HK, Shon HK, Son HY, Huh YM, Lee SW, Lee TG. TOF-SIMS analysis of an isocitrate dehydrogenase 1 mutation-associated oncometabolite in cancer cells. Biointerphases. 2018 Jan 30;13(3):03B404. doi: 10.1116/1.5013633. PMID: 29382206. 17: Zhang N, Zheng B, Yao X, Huang X, Du J, Shen Y, Huang Z, Chen J, Lin Q, Lan W, Lin W, Ma W. Identification and characterization of a novel mutant isocitrate dehydrogenase 1 inhibitor for glioma treatment. Biochem Biophys Res Commun. 2021 Apr 30;551:38-45. doi: 10.1016/j.bbrc.2021.02.112. Epub 2021 Mar 11. PMID: 33714758. 18: Khurshed M, Prades-Sagarra E, Saleh S, Sminia P, Wilmink JW, Molenaar RJ, Crezee H, van Noorden CJF. Hyperthermia as a Potential Cornerstone of Effective Multimodality Treatment with Radiotherapy, Cisplatin and PARP Inhibitor in IDH1-Mutated Cancer Cells. Cancers (Basel). 2022 Dec 17;14(24):6228. doi: 10.3390/cancers14246228. PMID: 36551714; PMCID: PMC9777513. 19: Li L, Paz AC, Wilky BA, Johnson B, Galoian K, Rosenberg A, Hu G, Tinoco G, Bodamer O, Trent JC. Treatment with a Small Molecule Mutant IDH1 Inhibitor Suppresses Tumorigenic Activity and Decreases Production of the Oncometabolite 2-Hydroxyglutarate in Human Chondrosarcoma Cells. PLoS One. 2015 Sep 14;10(9):e0133813. doi: 10.1371/journal.pone.0133813. PMID: 26368816; PMCID: PMC4569544. 20: Fujiwara H, Tateishi K, Kato H, Nakatsuka T, Yamamoto K, Tanaka Y, Ijichi H, Takahara N, Mizuno S, Kogure H, Matsubara S, Nakai Y, Koike K. Isocitrate dehydrogenase 1 mutation sensitizes intrahepatic cholangiocarcinoma to the BET inhibitor JQ1. Cancer Sci. 2018 Nov;109(11):3602-3610. doi: 10.1111/cas.13784. Epub 2018 Sep 17. PMID: 30156013; PMCID: PMC6215870.