Cudc-101- a single inhibitor with multiple effects
INTRODUCTION
Different cases of cancers are associated with modifications in the tyrosine kinase receptors and histone deacetylases. The malfunctioning of these proteins leads to hampered cellular responses. Various inhibitors which target the tyr kinase receptors have been designed. The success rate of these inhibitors against cancer has been rated to be low as cancers are dynamic in nature and they also offer resistance to these inhibitors. The causes of cancer may be different at different locations. CUDC-101 is a newly synthesized inhibitor which overcomes all these problems and is well known for its good success rates.
DESIGNING OF THE MULTI-TARGETED INHIBITOR CUDC-101
Cancers are usually associated with improper regulation of multiple signaling pathways. CUDC-101 is one such inhibitor which targets a number of proteins and can thereby inhibit the progression of different oncogenic pathways. It checks the survival growth and metastasis through different mechanisms. A combinatory method of using multiple drugs was earlier practiced, but this increases the toxicity under physiological conditions. CUDC-101 offers a novel approach where in a single inhibitor acts against multiple targets which are biochemically distinct. This reduces the cost and can be monitored easily [1]. A pharmacophore which targets EGFR (epidermal growth factor receptor) and HER2 (human epidermal growth factor receptor 2) was integrated with the unit which inhibits HDACs. As a result of this a new compound known as CUDC-101 was synthesized which affects multiple targets. Under in vitro conditions it showed an inhibitory effect against HDAC at a concentration of 4.4 nM. CUDC-101 inhibited the action of HER2 and EGFR at concentrations 15.7 and 2.4 respectively. This inhibitor was more potent than other inhibitors like SAHA, lapatinib and erlotinib or their combinations. It checked the proliferation and regression of tumor in xenograft models also. This inhibitor also proves a synergistic action between EGFR/HER2 and HDAC pathways and it is effective against these multiple pathways. Amongst the HDACs it inhibits the enzymes belonging to class I and II. It controls the progression of inhibitor resistant- tumor types also, under both in vitro and in vivo conditions. CUDC-101 also blocks certain other pathways like MET, HER3 and Akt [2].
CUDC-101: CHECKS THE ACTION OF HER2 IN BREAST CARCINOMA
The Type I, RTKs are required for various vital processes like survival, growth and differentiation into functional cells. ErbB family consists of EGFR, HER-2, Her-3, Her-4. These proteins are RTKs and have been well studied. Different tumors associated with lungs, breast, prostate glands, ovary etc have been associated with the hyper-expression of EGFR and ErbB-2. When the signal transduction due to these kinases is blocked, the proliferation of the tumor is checked [3]. Especially in case of breast cancers the signaling pathway originating from EGFR and moving through HER1/ HER2 gets affected. Constitutive phosphorylation of HER2 is often associated with some kinds of breast cancers. Hence inhibitors which target these EGFR-specific kinases like HER2 are highly potent in arresting the growth of breast cancer [4].
CONCLUSION
CUDC-101 shows a synergistic inhibition of HDAC and RTKs. It suppresses the kinase activity efficiently and reduced the transcription of mRNA simultaneously. As it has significant effect on multiple pathways it can arrest the growth of different cancers.
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. Núñez MC, Kimatrai M, et al. Novel substituted quinazolines for potent EGFR tyrosine kinase inhibitors. Curr Med Chem 2011; 18(7):943-63.
4. Moulder SL, Yakes FM, et al. Epidermal Growth Factor Receptor (Selumetinib) Tyrosine Kinase Inhibitor ZD1839 (Iressa) Inhibits HER2/neu (xl880)-overexpressing Breast Cancer Cells in Vitro and in Vivo1. Cancer Res 2001 Dec 15; 61(24):8887-95.
Related Posts:
BELINOSTAT (PXD101) – INHIBITS THE CANCEROUS GROWTH
VORINOSTAT (SAHA) – INHIBITS DIFFERENT KINDS OF TUMORS
Different cases of cancers are associated with modifications in the tyrosine kinase receptors and histone deacetylases. The malfunctioning of these proteins leads to hampered cellular responses. Various inhibitors which target the tyr kinase receptors have been designed. The success rate of these inhibitors against cancer has been rated to be low as cancers are dynamic in nature and they also offer resistance to these inhibitors. The causes of cancer may be different at different locations. CUDC-101 is a newly synthesized inhibitor which overcomes all these problems and is well known for its good success rates.
DESIGNING OF THE MULTI-TARGETED INHIBITOR CUDC-101
Cancers are usually associated with improper regulation of multiple signaling pathways. CUDC-101 is one such inhibitor which targets a number of proteins and can thereby inhibit the progression of different oncogenic pathways. It checks the survival growth and metastasis through different mechanisms. A combinatory method of using multiple drugs was earlier practiced, but this increases the toxicity under physiological conditions. CUDC-101 offers a novel approach where in a single inhibitor acts against multiple targets which are biochemically distinct. This reduces the cost and can be monitored easily [1]. A pharmacophore which targets EGFR (epidermal growth factor receptor) and HER2 (human epidermal growth factor receptor 2) was integrated with the unit which inhibits HDACs. As a result of this a new compound known as CUDC-101 was synthesized which affects multiple targets. Under in vitro conditions it showed an inhibitory effect against HDAC at a concentration of 4.4 nM. CUDC-101 inhibited the action of HER2 and EGFR at concentrations 15.7 and 2.4 respectively. This inhibitor was more potent than other inhibitors like SAHA, lapatinib and erlotinib or their combinations. It checked the proliferation and regression of tumor in xenograft models also. This inhibitor also proves a synergistic action between EGFR/HER2 and HDAC pathways and it is effective against these multiple pathways. Amongst the HDACs it inhibits the enzymes belonging to class I and II. It controls the progression of inhibitor resistant- tumor types also, under both in vitro and in vivo conditions. CUDC-101 also blocks certain other pathways like MET, HER3 and Akt [2].
CUDC-101: CHECKS THE ACTION OF HER2 IN BREAST CARCINOMA
The Type I, RTKs are required for various vital processes like survival, growth and differentiation into functional cells. ErbB family consists of EGFR, HER-2, Her-3, Her-4. These proteins are RTKs and have been well studied. Different tumors associated with lungs, breast, prostate glands, ovary etc have been associated with the hyper-expression of EGFR and ErbB-2. When the signal transduction due to these kinases is blocked, the proliferation of the tumor is checked [3]. Especially in case of breast cancers the signaling pathway originating from EGFR and moving through HER1/ HER2 gets affected. Constitutive phosphorylation of HER2 is often associated with some kinds of breast cancers. Hence inhibitors which target these EGFR-specific kinases like HER2 are highly potent in arresting the growth of breast cancer [4].
CONCLUSION
CUDC-101 shows a synergistic inhibition of HDAC and RTKs. It suppresses the kinase activity efficiently and reduced the transcription of mRNA simultaneously. As it has significant effect on multiple pathways it can arrest the growth of different cancers.
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. Núñez MC, Kimatrai M, et al. Novel substituted quinazolines for potent EGFR tyrosine kinase inhibitors. Curr Med Chem 2011; 18(7):943-63.
4. Moulder SL, Yakes FM, et al. Epidermal Growth Factor Receptor (Selumetinib) Tyrosine Kinase Inhibitor ZD1839 (Iressa) Inhibits HER2/neu (xl880)-overexpressing Breast Cancer Cells in Vitro and in Vivo1. Cancer Res 2001 Dec 15; 61(24):8887-95.
Related Posts:
BELINOSTAT (PXD101) – INHIBITS THE CANCEROUS GROWTH
VORINOSTAT (SAHA) – INHIBITS DIFFERENT KINDS OF TUMORS
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