CG200745 - CAS 936221-33-9
Catalog number: 936221-33-9
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
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Description:
CG200745 is a novel hydroxamate-based pan-histone deacetylase inhibitor (HDACI). Like other inhibitors, CG200745 has the hydroxamic acid moiety to bind zinc at the bottom of catalytic pocket. CG200745 inhibited deacetylation of histone H3 and tubulin as much as vorinostat and belinostat did. CG200745 also inhibited growth of prostate cancer cells, increased sub-G1 population, and activated caspase-9, -3 and -8 in LNCaP, DU145 and PC3 cells. These results indicate that CG200745 induces apoptosis. The preclinical results show that combination treatment with docetaxel and new HDACI, CG200745, potentiated anti-tumor effect in hormone-refractory prostate cancer (HRPC) cells via activation of apoptosis.
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Synonyms:
CG200745; CG-200745; CG 200745
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Current Developer:
University of Ulsan College of Medicine, South Korea
1.A novel histone deacetylase inhibitor, CG200745, potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1 and Bcl-XL.
Hwang JJ1, Kim YS, Kim T, Kim MJ, Jeong IG, Lee JH, Choi J, Jang S, Ro S, Kim CS. Invest New Drugs. 2012 Aug;30(4):1434-42. doi: 10.1007/s10637-011-9718-1. Epub 2011 Jul 20.
We synthesized a novel hydroxamate-based pan-histone deacetylase inhibitor (HDACI), CG200745 {(E)-2-(Naphthalen-1-yloxymethyl)-oct-2-enedioic acid 1-[(3-dimethylamino-propyl)-amide] 8-hydroxyamide]}. Like other inhibitors, for example vorinostat and belinostat, CG200745 has the hydroxamic acid moiety to bind zinc at the bottom of catalytic pocket. Firstly, we analyzed its inhibitory activity against histone deacetylase (HDAC) in hormone-dependent LNCaP cells and hormone-independent DU145 and PC3 cells. CG200745 inhibited deacetylation of histone H3 and tubulin as much as vorinostat and belinostat did. CG200745 also inhibited growth of prostate cancer cells, increased sub-G1 population, and activated caspase-9, -3 and -8 in LNCaP, DU145 and PC3 cells. These results indicate that CG200745 induces apoptosis. Next, we examined the effect of CG200745 on cell death induced by docetaxel in DU145 cells in vitro and in vivo. Compared to mono-treatment with each drug, pre-treatment of DU145 cells with docetaxel followed by CG200745 showed synergistic cytotoxicity, and increased the apoptotic sub-G1 population, caspase activation, and tubulin acetylation.
2.Epigenetic modulation with HDAC inhibitor CG200745 induces anti-proliferation in non-small cell lung cancer cells.
Chun SM1, Lee JY2, Choi J1, Lee JH3, Hwang JJ2, Kim CS4, Suh YA2, Jang SJ5. PLoS One. 2015 Mar 17;10(3):e0119379. doi: 10.1371/journal.pone.0119379. eCollection 2015.
Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we investigated the therapeutic potentials and mechanistic roles of the recently developed histone deacetylase inhibitor, CG200745, in non-small cell lung cancer cells. Treatment with CG200745 increased the global level of histone acetylation, resulting in the inhibition of cell proliferation. ChIP-on-chip analysis with an H4K16ac antibody showed altered H4K16 acetylation on genes critical for cell growth inhibition, although decreased at the transcription start site of a subset of genes. Altered H4K16ac was associated with changes in mRNA expression of the corresponding genes, which were further validated in quantitative RT-PCR and western blotting assays. Our results demonstrated that CG200745 causes NSCLC cell growth inhibition through epigenetic modification of critical genes in cancer cell survival, providing pivotal clues as a promising chemotherapeutics against lung cancer.
3.Novel histone deacetylase inhibitor CG200745 induces clonogenic cell death by modulating acetylation of p53 in cancer cells.
Oh ET1, Park MT, Choi BH, Ro S, Choi EK, Jeong SY, Park HJ. Invest New Drugs. 2012 Apr;30(2):435-42. doi: 10.1007/s10637-010-9568-2. Epub 2010 Oct 27.
Histone deacetylase (HDAC) plays an important role in cancer onset and progression. Therefore, inhibition of HDAC offers potential as an effective cancer treatment regimen. CG200745, (E)-N(1)-(3-(dimethylamino)propyl)-N(8)-hydroxy-2-((naphthalene-1-loxy)methyl)oct-2-enediamide, is a novel HDAC inhibitor presently undergoing a phase I clinical trial. Enhancement of p53 acetylation by HDAC inhibitors induces cell cycle arrest, differentiation, and apoptosis in cancer cells. The purpose of the present study was to investigate the role of p53 acetylation in the cancer cell death caused by CG200745. CG200745-induced clonogenic cell death was 2-fold greater in RKO cells expressing wild-type p53 than in p53-deficient RC10.1 cells. CG200745 treatment was also cytotoxic to PC-3 human prostate cancer cells, which express wild-type p53. CG200745 increased acetylation of p53 lysine residues K320, K373, and K382. CG200745 induced the accumulation of p53, promoted p53-dependent transactivation, and enhanced the expression of MDM2 and p21(Waf1/Cip1) proteins, which are encoded by p53 target genes.
4.First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies.
Kim KP1, Park SJ1, Kim JE1, Hong YS1, Lee JL1, Bae KS2, Cha H3, Kwon SK3, Ro S3, Cho J3, Kim TW4. Invest New Drugs. 2015 Oct;33(5):1048-57. doi: 10.1007/s10637-015-0262-2. Epub 2015 Jun 17.
PURPOSE: The aim of the present study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single and multiple doses of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies.
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