Due to clinical therapeutic requirements, drugs of targeting several targets are profoundly developed. CUDC-101[1] was designed under these clinical background as our previous described (please view related posts). However, the basic understanding about CUDC-101 is very little. This blog aims to introduce more information about it. Integration of inhibitory functional elements of HDAC, EGFR, and HER2 from several other small molecules into one single small molecule formed the multitargeted compound CUDC-101. In a series of kinases assays, CUDC-101 Fig. 1) not only prevents the function of epidermal growth factor receptor (EGFR) but also blocks the activities of the receptor tyrosine kinase HER2 as well as actions of class I and class II histone deacetylases (HDACs) with high selective potency with IC50 values of 2.4, 16.4, and 4.2nM, respectively. Surprisingly, CUDC-101 effectively blocks the actions of the erlotinib-resistant EGFR mutant T790M. However, in assays of a panel of other kinases for evaluate the selectivity of CUDC-101, it is presented that the inhibitory effects of CUDC-101 on KDR (VEGFR2), Lyn, Lck, Abl-1, FGFR-2, Flt-3, and Ret were weak with IC50 values of 0.85, 0.84, 5.9, 2.89, 3.43, 1.5, and 3.2 M, respectively. In vitro assays, CUDC-101 significantly prevented the progression, proliferation and survival of a wide extent of tumor cell lines, such as A431 cells, H292 cells and BT-474 cells. In vivo xenograft animal models, CUDC-101 also decreased the volume of tumors and improved the survival rate of model animals. Recent studies suggested that CUDC-101 indirectly attenuates the survival Akt signaling pathway, HER3 signaling pathway, and MET signaling pathway in addition to directly inhibiting both EGFR and HER2 signaling pathways.[2] As far as we know, CUDC-101 is a multitargetd small-molecular compound which is a potent receptor tyrosine kinase (including EGFR and HER2 et al.) and histone deacetylase (including calss I and class II) inhibitor with extremely low half-inhibitory concentration up to nanomole. However, whether the inhibitory effects of CUDC-101 on receptor tyrosine kinase (RTK) and histone deacetylase (HDACs) are significant additive or synergistic remains unclear. In a study, combined blockage of histone deacetylase and EGFR signaling pathways mediated by two tool compounds, which were named as vorinost (a potent histone deacetylase inhibitor) and erlotinib (an selective EGFR kinase inhibitor), achieves considerably good synergy in the used MDA-MB-468 breast cancer cell line. They may often introduce adverse effects associated to pharmacokinetics and toxicity of applied drugs, and related to patient compliance. On the other hand, one kind of drugs with multiple preventive effects were widely developed because of their more advantages including pharmacokinetic simplicity and lower cost. Thus, a novel therapeutic strategy based on a single small molecular compound, which act on two or more biochemically various but related targets of the same gene family was hypothesized. Lots of specific inhibitors (such as erlotinib, gefitinib, and lapatinib) targeting HER family receptor tyrosine kinases (RTK) including histone deacetylase (HDAC) and human epidermal growth factor receptor (HER) kinases et al. have become important therapeutic agents for many types of solid tumor cancers in patients. However, only a small part of patients can take these drugs for the molecular heterogeneity among and within carcinomas. To overcome the low efficacy and induced resistance to RTK inhibitors, several strategies have been designed. It seems that the regulation of RTK pathways by the prevention of HDACs is a particularly promising project. CUDC-101 is designed and synthesized under the kind of background.[1] References: [1] J Med Chem. 2010 Mar 11;53(5):2000-9. [2] Cancer Res. 2010 May 1;70(9):3647-56. Related posts Single-target and multitargted strategies
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