CHS-828 | GMX 1778 | CAS#200484-11-3 | NAMPT inhibitor

MedKoo Cat#: 200776 | Name: CHS-828

Description:

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

CHS-828, also known as GMX-1778, is a potent and selective NAMPT inhibitor. CHS-828 inhibits cellular synthesis of NAD. CHS 828 kill tumour cells by inhibiting the nuclear factor-kappaB translocation but unlikely through down-regulation of proteasome. CHS 828 has shown promising anticancer activity in experimental tumor models and primary cultures of cancer cells from patients. CHS 828 showed a synergistic effect with melphalan in 67%, doxorubicin in 47%, etoposide in 38% and Ara-C in 14% of AML samples.

Chemical Structure

CHS-828

CAS#200484-11-3 (free)

Theoretical Analysis

MedKoo Cat#: 200776

Name: CHS-828

CAS#: 200484-11-3 (free)

Chemical Formula: C19H22ClN5O

Exact Mass: 371.1513

Molecular Weight: 371.86

Elemental Analysis: C, 61.37; H, 5.96; Cl, 9.53; N, 18.83; O, 4.30

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 300.00	Ready to ship
50mg	USD 500.00	Ready to ship
100mg	USD 750.00	Ready to ship
250mg	USD 1,450.00	Ready to ship

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Related CAS #

1160589-73-0 (nicotinate) 200484-11-3 (free)

Synonym

CHS 828; CHS828; CHS-828; GMX-1778; GMX1778; GMX 1778.

IUPAC/Chemical Name

(E)-1-(6-(4-chlorophenoxy)hexyl)-2-cyano-3-(pyridin-4-yl)guanidine

InChi Key

BOIPLTNGIAPDBY-UHFFFAOYSA-N

InChi Code

InChI=1S/C19H22ClN5O/c20-16-5-7-18(8-6-16)26-14-4-2-1-3-11-23-19(24-15-21)25-17-9-12-22-13-10-17/h5-10,12-13H,1-4,11,14H2,(H2,22,23,24,25)

SMILES Code

N#C/N=C(NC1=CC=NC=C1)\NCCCCCCOC2=CC=C(Cl)C=C2

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

>5 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

Review of Phase I trials of CHS-828. Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20-80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3-4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials. Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low. (source: Cancer Chemother Pharmacol. 2010 May;65(6):1165-72 ). Phase I study of CHS-828. CHS 828 was given orally once every 3 weeks. The starting dose was 50 mg, which was escalated to 500 mg. A total of 107 courses was administered to 37 patients. At the 500-mg dose level, two of three patients experienced dose-limiting toxicities (DLT) (grade 3 mucositis and grade 4 thrombocytopenia), establishing this as the MTD. One of seven patients treated at 420 mg dose experienced DLT (grade 4 leucopenia, grade 4 mucositis and grade 4 diarrhoea), and this was considered the recommended dose for phase II studies. Vomiting, haematuria, leucopenia and thrombocytopenia were other significant toxicities. The pharmacokinetics of CHS 828 showed large variations both between and within patients. No objective responses were seen. A dose of 420 mg of CHS 828 administered every 3 weeks is the recommended dose, while 500 mg is the MTD. (source: Eur J Cancer. 2005 Mar;41(5):702-7.). Phase I study of CHS-828. (source: Eur J Cancer. 2005 Mar;41(5):702-7.).

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#CRB51019

QC Data

View QC data: current batch, Lot#CRB51019

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

CHS-828 (GMX1778) is a competitive inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), with an IC50 less than 25 nM.

In vitro activity:

In this report, GMX1778 induces ROS, specifically superoxide radicals evidenced by DHE oxidation, via decreasing the cellular level of NAD+, NADP+, NADH, and NADPH. The results measuring apoptosis by annexin V staining after treatment with GMX1778 in the cell lines tested are consistent with the dual roles of p53 in response to ROS. In addition to p53, the induced ROS levels by GMX1778 were further suppressed when the NAD+ levels were restored by exogenously adding niacin to NAPRT1-expressing cancer cells tested. Notably, the ROS were not induced by GMX1778 within 48 h of post-GMX1778 exposure in normal (HMEC) or immortalized cells (MCF10A) tested in the absence of NA. Reference: J Biol Chem. 2012 Jun 22; 287(26): 22408–22417. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381200/

In vivo activity:

Four days after intratumoral injection of GMX1778 MP (microparticles), there was a significant increase in the number of PD-L1-positive cells within GL261 tumors as compared to two controls, PBS and blank MP not containing drug (Fig. 2B, C). Co-immunofluorescence of PD-L1 and glioma marker nestin or macrophage marker Arg1 showed that upregulation of PD-L1 occurred in both GBM cells and glioma-infiltrating macrophages (Fig. 2D, E). Thus, local MP delivery of NAMPT inhibitor induces upregulation of immune checkpoint PD-L1 in murine GBM. Reference: Cancer Res. 2020 Nov 15; 80(22): 5024–5034. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669613/

	Solvent	mg/mL	mM
Solubility
	DMSO	43.8	117.79
	DMSO:PBS (pH 7.2) (1:2)	0.3	0.89
	DMF	25.0	67.23
	Ethanol	0.5	1.34

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 371.86 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. Cerna D, Li H, Flaherty S, Takebe N, Coleman CN, Yoo SS. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) activity by small molecule GMX1778 regulates reactive oxygen species (ROS)-mediated cytotoxicity in a p53- and nicotinic acid phosphoribosyltransferase1 (NAPRT1)-dependent manner. J Biol Chem. 2012 Jun 22;287(26):22408-17. doi: 10.1074/jbc.M112.357301. Epub 2012 May 8. PMID: 22570471; PMCID: PMC3381200. 2. Watson M, Roulston A, Bélec L, Billot X, Marcellus R, Bédard D, Bernier C, Branchaud S, Chan H, Dairi K, Gilbert K, Goulet D, Gratton MO, Isakau H, Jang A, Khadir A, Koch E, Lavoie M, Lawless M, Nguyen M, Paquette D, Turcotte E, Berger A, Mitchell M, Shore GC, Beauparlant P. The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors. Mol Cell Biol. 2009 Nov;29(21):5872-88. doi: 10.1128/MCB.00112-09. Epub 2009 Aug 24. PMID: 19703994; PMCID: PMC2772749. 3. Li M, Kirtane AR, Kiyokawa J, Nagashima H, Lopes A, Tirmizi ZA, Lee CK, Traverso G, Cahill DP, Wakimoto H. Local Targeting of NAD+ Salvage Pathway Alters the Immune Tumor Microenvironment and Enhances Checkpoint Immunotherapy in Glioblastoma. Cancer Res. 2020 Nov 15;80(22):5024-5034. doi: 10.1158/0008-5472.CAN-20-1094. Epub 2020 Sep 30. Erratum in: Cancer Res. 2021 Apr 1;81(7):1922. PMID: 32998997; PMCID: PMC7669613. 4. Shankar GM, Kirtane AR, Miller JJ, Mazdiyasni H, Rogner J, Tai T, Williams EA, Higuchi F, Juratli TA, Tateishi K, Koerner MVA, Tummala SS, Fink AL, Penson T, Schmidt SP, Wojtkiewicz GR, Baig A, Francis JM, Rinne ML, Batten JM, Batchelor TT, Brastianos PK, Curry WT Jr, Barker FG 2nd, Jordan JT, Iafrate AJ, Chi AS, Lennerz JK, Meyerson M, Langer R, Wakimoto H, Traverso G, Cahill DP. Genotype-targeted local therapy of glioma. Proc Natl Acad Sci U S A. 2018 Sep 4;115(36):E8388-E8394. doi: 10.1073/pnas.1805751115. Epub 2018 Aug 6. PMID: 30082399; PMCID: PMC6130372.

In vitro protocol:

In vivo protocol:

1. Li M, Kirtane AR, Kiyokawa J, Nagashima H, Lopes A, Tirmizi ZA, Lee CK, Traverso G, Cahill DP, Wakimoto H. Local Targeting of NAD+ Salvage Pathway Alters the Immune Tumor Microenvironment and Enhances Checkpoint Immunotherapy in Glioblastoma. Cancer Res. 2020 Nov 15;80(22):5024-5034. doi: 10.1158/0008-5472.CAN-20-1094. Epub 2020 Sep 30. Erratum in: Cancer Res. 2021 Apr 1;81(7):1922. PMID: 32998997; PMCID: PMC7669613. 2. Shankar GM, Kirtane AR, Miller JJ, Mazdiyasni H, Rogner J, Tai T, Williams EA, Higuchi F, Juratli TA, Tateishi K, Koerner MVA, Tummala SS, Fink AL, Penson T, Schmidt SP, Wojtkiewicz GR, Baig A, Francis JM, Rinne ML, Batten JM, Batchelor TT, Brastianos PK, Curry WT Jr, Barker FG 2nd, Jordan JT, Iafrate AJ, Chi AS, Lennerz JK, Meyerson M, Langer R, Wakimoto H, Traverso G, Cahill DP. Genotype-targeted local therapy of glioma. Proc Natl Acad Sci U S A. 2018 Sep 4;115(36):E8388-E8394. doi: 10.1073/pnas.1805751115. Epub 2018 Aug 6. PMID: 30082399; PMCID: PMC6130372.

1: von Heideman A, Berglund A, Larsson R, Nygren P. Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data. Cancer Chemother Pharmacol. 2010 May;65(6):1165-72. doi: 10.1007/s00280-009-1125-3. Epub 2009 Sep 30. PubMed PMID: 19789873. 2: LÃ¶vborg H, Burman R, Gullbo J. Structure-activity relationship analysis of cytotoxic cyanoguanidines: selection of CHS 828 as candidate drug. BMC Res Notes. 2009 Jun 29;2:114. doi: 10.1186/1756-0500-2-114. PubMed PMID: 19563661; PubMed Central PMCID: PMC2709656. 3: Olesen UH, Christensen MK, BjÃ¶rkling F, JÃ¤Ã¤ttelÃ¤ M, Jensen PB, Sehested M, Nielsen SJ. Anticancer agent CHS-828 inhibits cellular synthesis of NAD. Biochem Biophys Res Commun. 2008 Mar 21;367(4):799-804. doi: 10.1016/j.bbrc.2008.01.019. Epub 2008 Jan 15. PubMed PMID: 18201551. 4: Hassan SB, LÃ¶vborg H, Lindhagen E, Karlsson MO, Larsson R. CHS 828 kill tumour cells by inhibiting the nuclear factor-kappaB translocation but unlikely through down-regulation of proteasome. Anticancer Res. 2006 Nov-Dec;26(6B):4431-6. PubMed PMID: 17201165. 5: Johanson V, Arvidsson Y, KÃ¶lby L, Bernhardt P, SwÃ¤rd C, Nilsson O, Ahlman H. Antitumoural effects of the pyridyl cyanoguanidine CHS 828 on three different types of neuroendocrine tumours xenografted to nude mice. Neuroendocrinology. 2005;82(3-4):171-6. Epub 2006 Feb 24. PubMed PMID: 16508338. 6: Friberg LE, Hassan SB, Lindhagen E, Larsson R, Karlsson MO. Pharmacokinetic-pharmacodynamic modelling of the schedule-dependent effect of the anti-cancer agent CHS 828 in a rat hollow fibre model. Eur J Pharm Sci. 2005 May;25(1):163-73. PubMed PMID: 15854812. 7: Ravaud A, Cerny T, Terret C, Wanders J, Bui BN, Hess D, Droz JP, Fumoleau P, Twelves C. Phase I study and pharmacokinetic of CHS-828, a guanidino-containing compound, administered orally as a single dose every 3 weeks in solid tumours: an ECSG/EORTC study. Eur J Cancer. 2005 Mar;41(5):702-7. PubMed PMID: 15763645. 8: Olsen LS, Hjarnaa PJ, Latini S, Holm PK, Larsson R, Bramm E, Binderup L, Madsen MW. Anticancer agent CHS 828 suppresses nuclear factor-kappa B activity in cancer cells through downregulation of IKK activity. Int J Cancer. 2004 Aug 20;111(2):198-205. PubMed PMID: 15197771. 9: LÃ¶vborg H, Nygren P, Larsson R. Multiparametric evaluation of apoptosis: effects of standard cytotoxic agents and the cyanoguanidine CHS 828. Mol Cancer Ther. 2004 May;3(5):521-6. PubMed PMID: 15141009.