CHS-828 - CAS 200484-11-3
Catalog number:
200484-11-3
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
COA:
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Targets:
Nampt
Description:
CHS-828 is a synthetic guanidine-based small anticancer molecule. CHS 828 was found to exert potent cytotoxic effects in human breast and lung cancer cell lines, with lesser effects on normal fibroblasts and endothelial cells. In nude mice bearing human tumor xenografts, CHS 828, at doses from 20 to 50 mg/kg/day p.o., inhibited the growth of MCF-7 breast cancer tumors and caused regression of NYH small cell lung cancer tumors. Oral administration of CHS 828 once weekly improved efficacy without increasing toxicity. CHS 828 was found to compare favorably with established chemotherapeutic agents such as cyclophosphamide, etoposide, methotrexate, and paclitaxel. In mice with NYH tumors, long-term survival (>6 months) was observed after treatment with CHS 828 was stopped. CHS 828 is an effective new antitumor agent, with a potentially new mechanism of action. CHS-828 appeared to kill cancer cells by depleting NAD. CHS 828 is presently being tested in Phase I clinical trials in collaboration with the European Organization for Research and Treatment of Cancer.
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Synonyms:
CHS 828; CHS-828; GMX 1778.
MSDS:
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Current Developer:
Leo Pharmaceutical Products, Ballerup, Denmark.
1.Oligo-carrageenan kappa-induced reducing redox status and increase in TRR/TRX activities promote activation and reprogramming of terpenoid metabolism in Eucalyptus trees.
González A1, Gutiérrez-Cutiño M2, Moenne A3. Molecules. 2014 Jun 5;19(6):7356-67. doi: 10.3390/molecules19067356.
In order to analyze whether the reducing redox status and activation of thioredoxin reductase (TRR)/thioredoxin(TRX) system induced by oligo-carrageenan (OC) kappa in Eucalyptus globulus activate secondary metabolism increasing terpenoid synthesis, trees were sprayed on the leaves with water, with OC kappa, or with inhibitors of NAD(P)H, ascorbate (ASC) and (GSH) synthesis and TRR activity, CHS-828, lycorine, buthionine sulfoximine (BSO) and auranofine, respectively, and with OC kappa and cultivated for four months. The main terpenoids in control Eucalyptus trees were eucalyptol (76%), α-pinene (7.4%), aromadendrene (3.6%), silvestrene (2.8%), sabinene (2%) and α-terpineol (0.9%). Treated trees showed a 22% increase in total essential oils as well as a decrease in eucalyptol (65%) and sabinene (0.8%) and an increase in aromadendrene (5%), silvestrene (7.8%) and other ten terpenoids. In addition, treated Eucalyptus showed seven de novo synthesized terpenoids corresponding to carene, α-terpinene, α-fenchene, γ-maaliene, spathulenol and α-camphenolic aldehyde.
2.Synthesis and anticancer evaluation of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-triazoles and Mannich bases.
Megally Abdo NY1, Kamel MM. Chem Pharm Bull (Tokyo). 2015;63(5):369-76. doi: 10.1248/cpb.c15-00059.
A series of 5-(pyridin-4-yl)-N-substituted-1,3,4-oxadiazol-2-amines (3a-d), 5-(pyridin-4-yl)-N-substituted-1,3,4-thiadiazol-2-amines (4a-d) and 5-(pyridin-4-yl)-4-substituted-1,2,4-triazole-3-thiones (5a-d) were obtained by the cyclization of hydrazinecarbothioamide derivatives 2a-d derived from isonicotinic acid hydrazide. Aminoalkylation of compounds 5a-d with formaldehyde and various secondary amines furnished the Mannich bases 6a-p. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data and elemental analyses. All the compounds were screened for their in vitro anticancer activity against six human cancer cell lines and normal fibroblast cells. Sixteen of the tested compounds exhibited significant cytotoxicity against most cell lines. Among these derivatives, the Mannich bases 6j, 6m and 6p were found to exhibit the most potent activity. The Mannich base 6m showed more potent cytotoxic activity against gastric cancer NUGC (IC50=0.
3.Retinal toxicity, in vivo and in vitro, associated with inhibition of nicotinamide phosphoribosyltransferase.
Zabka TS1, Singh J2, Dhawan P2, Liederer BM2, Oeh J2, Kauss MA2, Xiao Y2, Zak M2, Lin T2, McCray B2, La N2, Nguyen T2, Beyer J2, Farman C2, Uppal H2, Dragovich PS2, O'Brien T2, Sampath D2, Misner DL1. Toxicol Sci. 2015 Mar;144(1):163-72. doi: 10.1093/toxsci/kfu268. Epub 2014 Dec 11.
Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein with intra- and extra-cellular functions as an enzyme, cytokine, growth factor, and hormone. NAMPT is of interest for oncology, because it catalyzes the rate-limiting step in the salvage pathway to generate nicotinamide adenine dinucleotide (NAD), which is considered a universal energy- and signal-carrying molecule involved in cellular energy metabolism and many homeostatic functions. This manuscript describes NAMPT inhibitor-induced retinal toxicity that was identified in rodent safety studies. This toxicity had a rapid onset and progression and initially targeted the photoreceptor and outer nuclear layers. Using in vivo safety and efficacy rodent studies, human and mouse cell line potency data, human and rat retinal pigmented epithelial cell in vitro systems, and rat mRNA expression data of NAMPT, nicotinic acid phosphoribosyltransferase, and nicotinamide mononucleotide adenylyltransferease (NMNAT) in several tissues from rat including retina, we demonstrate that the retinal toxicity is on-target and likely human relevant.
4.Synthesis and Cytotoxic Evaluation of Pyran, Dihydropyridine and Thiophene Derivatives of 3-Acetylcoumarin.
Mohareb RM1, Megally Abdo NY. Chem Pharm Bull (Tokyo). 2015;63(9):678-87. doi: 10.1248/cpb.c15-00115.
A series of coumarin analogues bearing 4H-pyran rings 2a-d, 11a-d and 1,4-dihydropyridine rings 3a-d, 12a-d at position 3 were synthesized starting from either 3-acetyl coumarin (1) or the coumarin acetohydrazide derivative 4. Condensation of 3-acetylcoumarin (1) with 2-cyanoacetohydrazide afforded 2-cyano-N'-{1-[2-oxo-2H-chromen-3-yl]ethylidene}acetohydrazide (4). Reaction of compound 4 with elemental sulfur and either malononitrile or ethyl cyanoacetate afforded the thiophene derivatives 8 and 9, respectively. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data and elemental analyses. All synthesized compounds were screened for their in vitro anticancer activity against six human cancer cell lines and normal fibroblasts. Several compounds showed potent inhibition with an IC50 value of ˂870 nM. Compound 3d exhibited equivalent cytotoxic effect as the standard CHS 828 against a breast cancer cell line (IC50 value=18 nM).
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CAS 200484-11-3 CHS-828

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