Tuesday, March 13, 2012



An elaborate research on cancers has shown that they are mostly an outcome of the up regulated MAPK pathway or due to the variations in the levels of HDAC enzymes. Inhibitors which target these pathways either check the uncontrolled progression of this pathway or increase the acetylation of the histone proteins. A single inhibitor which can regulate all these effects would be highly beneficial. CUDC-101 was discovered to be a single inhibitor with multiple effects.


A pharmacophore having EGFR and HER2 inhibitor properties was selected and HDAC inhibitor functionality was integrated into it. This invention - CUDC-101, was further subjected to clinical development. It inhibited HDAC at a concentration of 4.4 nM, EGFR at 2.4 nM, and HER2 at 15.7 nM. It was more potent when compared to vorinostat and other RTK inhibitors. It interferes with multiple pathways and checked the proliferation of various cancer cell lines [1].


Even during the course of treatment many tumors develop new mis-regulated survival and growth pathways. Hence a combination of inhibitors or a single inhibitor which can check the growth of tumor and control the process of metastasis are very beneficial. When multiple inhibitors are used there are chances of adverse side effects. A single inhibitor with multiple targets can solve this problem. During the first phases of research the molecule which can inhibit HER (human epidermal growth factor receptor) kinases and contains HDAC inhibitor properties was designed. Later on the novel molecule CUDC-101 was discovered which targeted HER2, HDACs belonging to class I and II and EGFR (epidermal growth factor receptor). Due to its multiple effects it suppressed the growth of a large variety of tumors. It indirectly regulates the HER3, Akt and MET pathways also [2].


The receptors of the HER family are inhibited by inhibitors like gefitinib, erlotinib and lapatinib, which are also known as RTK inhibitors. These inhibitors are highly efficient in case of solid tumors. But the heterogeneity of tumors poses a problem in treatment using the above mentioned inhibitors. The efficacy of these inhibitors is further reduced due to the resistance offered during the course of treatment. CUDC-101 is effective even in those cells which are resistant to erlotinib and lapatinib [2].


Colon cancer cells show a coexpression of EGFR and when they heterodimerize, the signal transduction pathways get diversified. GW572016 is a dual inhibitor which inhibits both ErbB2 and EGFR kinases. AG1478 is a selective EGFR inhibitor and AG879 acts specifically on ErbB2 kinase. A combination of these inhibitors checked the growth and stimulated the process of apoptosis. GW572016 is a single inhibitor which shows more potent changes at lower concentrations. This research shows that a single agent is more effective against EGFR and ErbB2 rather than a combination of two inhibitors [3]. Breast cancers are usually associated with abnormal signaling by EGF receptor. In fact a constitutive phosphorylation of HER2 is seen in most cases of breast cancers. Hence inhibitors which can target EGFR can also modulate the expression of HER2 [4].


In summary CUDC-101 is a single inhibitor which modulates multiple pathways by targeting multiple kinases. This inhibitor has a high therapeutic potential.


1. 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.
2. 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
3. Zhou Y, Li S, et al. Blockade of EGFR and ErbB2 by the novel dual EGFR and ErbB2 tyrosine kinase inhibitor GW572016 sensitizes human colon carcinoma GEO cells to apoptosis. Cancer Res 2006 Jan 1; 66(1):404-11.
4. 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.

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