CUDC-101 IS AN INHIBITOR WITH MULTIPLE TARGETS
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Posted On :
Jan-04-2012
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Article Word Count :
769
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CUDC-101 is a novel compound which inhibits multiple targets. The effect of this inhibitor is on variety of protein groups for example receptors of kinases, different growth factor receptors like EGFR and HER2, in tumor cells. This is an efficient inhibitor of both classes of HDACs (class I and II).
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INTRODUCTION
CUDC-101 is a novel compound which inhibits multiple targets. The effect of this inhibitor is on variety of protein groups for example receptors of kinases, different growth factor receptors like EGFR and HER2, in tumor cells. This is an efficient inhibitor of both classes of HDACs (class I and II). Hence this inhibitor is a multi-targeted atnti-cancer drug. This chemical is under clinical trials for different pharmacological effects.
MECHANISM OF ACTION
CUDC-101 functions as an inhibitor of histone deacetylase. It functions like built in, that is this compound is designed in such a way to inhibit the functions of HDAC. The tiny structure has all the important residues which can bind and inhibit the working of HDAC, EGFR and HER2. The target of this molecule is to disturb the main regulators of these signaling pathways (EGFR, HDAC signaling pathways). Aside from this it is also able to block or stop many counterbalancing pathways for example HER3, MET and AKT (protein kinase B) [1].
EFFECT ON DIFFERENT KINASES
CUDC-101 has high potency to inhibit HER2, EGFR kinases and HDAC at different concentration, 16.4, 2.4 and 4.2 nmol per liter respectively. A dose dependent pattern like in case of other HDAC inhibitors was noted and when this compound inhibited the process of autophosphorylation of EGFR. Inhibition of HER2 phosphorylation has also been reported by it. These results clearly show the action mechanism of CUDC-101 on pathways of HDAC and RTK in cancerous cell cultures. Although this molecule has a minute inhibition effect on Lck (lymphocyte-specific protein tyrosine kinase), Abl-1 (Abelson murine leukemia viral oncogene homolog 1), Lyn, Ret and FGFR-2 kinases. These findings suggest about the specific and targeted action on HER2 and EGFR [1] [2].
HISTONE ACETYLATION
CUDC-101 also increases the process of acetylation in H3 and H4 histones in cancer or tumor cell lines [1]. This substance was also able to enhance the nonhistone acetylation of different proteins like p53 and α-tubulin and HDAC substrates.
ROLE IN BREAST CANCER TREATMENT
A good number of cancer types were analyzed to be linked with over expression of ErbB-2 as well as EGFR genes. The normal cell functions and processes like cell survival, normal growth and differentiation are done by RTKs type I. The proteins of RTKs include HER-2, EGFR and Her-4 and a lot of work has been done on these proteins. The high expression of EGFR and ErbB-2 are found to be present in case of different tumors like breast, lungs, prostat and ovary tumor cells. The inhibitor checks the tumor growth by inhibiting functions of these kinases [4]. Hence CUDC-101 is a kinase inhibitor. Inhibition of different kinases and up-regulation of HER2 was found to be important to stop the proliferation of breast cancer cells [3]. The combination of CUDC-101 and cabozantinib can be used against breast cancer.
The activity of CUD-101 for the inhibition of RTK and HDAC was non additive. The research findings showed that this molecule is not dose dependent for proper action. Hence this drug can be used alone as well against many different carcinogenic targets or pathways necessary for the cell survival [1].
CONCLUSION
The compound has simultaneously acted as a kinase inhibitor as well as down regulator of different genes. Like other HDAC inhibitors for example it also suppresses the different signaling pathways important for cell survival. In this case RTK and Akt pathways are affected by this inhibitor. This molecule work synergistically which means this compound is mostly not dose dependent for its action. Hence a lethal compound for tumor and cancer cells because of the unique property of inhibiting multiple signaling pathways.
REFERENCES
1. Bao R, Tao X, et al. CUDC-101, a Multitargeted Inhibitor of Histone Deacetylase, Epidermal Growth Factor Receptor, and Human Epidermal Growth Factor Receptor 2, Exerts Potent Anticancer Activity. Cancer Res 2010 May 1; 70; 3647
2. Cai X, Zhai HX, et al. Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDc-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J Med Chem 2010 Mar 11; 53(5):2000-9.
3. Moulder SL, Yakes FM, et al. Epidermal Growth Factor Receptor (HER1) Tyrosine Kinase Inhibitor ZD1839 (Iressa) Inhibits HER2/neu (erbB2)-overexpressing Breast Cancer Cells in Vitro and in Vivo1. Cancer Res 2001 Dec 15; 61(24):8887-95.
4. Núñez MC, Kimatrai M, et al. Novel substituted quinazolines for potent EGFR tyrosine kinase inhibitors. Curr Med Chem 2011; 18(7):943-63.
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