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1.
Clin Cancer Res ; 18(15): 4104-13, 2012 Aug 01.
Article in English | MEDLINE | ID: mdl-22693356

ABSTRACT

PURPOSE: Given that histone deacetylase (HDAC) inhibitors are known to induce multiple epigenetic modifications affecting signaling networks and act synergistically with phosphatidylinositol 3-kinase (PI3K) inhibitors, we developed a strategy to simultaneously inhibit HDACs and PI3K in cancer cells. EXPERIMENTAL DESIGN: We constructed dual-acting inhibitors by incorporating HDAC inhibitory functionality into a PI3K inhibitor pharmacophore. CUDC-907, a development candidate selected from these dual inhibitors, was evaluated in vitro and in vivo to determine its pharmacologic properties, anticancer activity, and mechanism of action. RESULTS: CUDC-907 potently inhibits class I PI3Ks as well as classes I and II HDAC enzymes. Through its integrated HDAC inhibitory activity, CUDC-907 durably inhibits the PI3K-AKT-mTOR pathway and compensatory signaling molecules such as RAF, MEK, MAPK, and STAT-3, as well as upstream receptor tyrosine kinases. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells. CONCLUSIONS: CUDC-907 may offer improved therapeutic benefits through simultaneous, sustained disruption of multiple oncogenic signaling networks.


Subject(s)
Enzyme Inhibitors/pharmacology , Histone Deacetylases/metabolism , Morpholines/pharmacology , Neoplasms/drug therapy , Phosphatidylinositol 3-Kinase/metabolism , Pyrimidines/pharmacology , Signal Transduction/drug effects , Animals , Apoptosis/drug effects , Blotting, Western , Caspase 3/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Enzyme Activation/drug effects , Female , HCT116 Cells , Histone Deacetylase Inhibitors/pharmacology , Humans , Hydroxamic Acids/pharmacology , Mice , Mice, Nude , Mice, SCID , Neoplasms/metabolism , Neoplasms/pathology , Phosphoinositide-3 Kinase Inhibitors , Quinazolines/pharmacology , Sf9 Cells , Tumor Burden/drug effects , Vorinostat , Xenograft Model Antitumor Assays
2.
Cancer Res ; 70(9): 3647-56, 2010 May 01.
Article in English | MEDLINE | ID: mdl-20388807

ABSTRACT

Receptor tyrosine kinase inhibitors have recently become important therapeutics for a variety of cancers. However, due to the heterogeneous and dynamic nature of tumors, the effectiveness of these agents is often hindered by poor response rates and acquired drug resistance. To overcome these limitations, we created a novel small molecule, CUDC-101, which simultaneously inhibits histone deacetylase and the receptor kinases epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in cancer cells. Because of its integrated histone deacetylase inhibition, CUDC-101 synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors. CUDC-101 displayed potent antiproliferative and proapoptotic activities against cultured and implanted tumor cells that are sensitive or resistant to several approved single-targeted drugs. Our results show that CUDC-101 has the potential to dramatically improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents. Further, they provide a framework to create individual small molecules that simultaneously antagonize multiple biochemically distinct oncogenic targets, suggesting a general paradigm to surpass conventional, single-target cancer therapeutics. Cancer Res; 70(9); 3647-56. (c)2010 AACR.


Subject(s)
ErbB Receptors/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Quinazolines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Animals , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Cell Growth Processes/drug effects , Cell Line, Tumor , ErbB Receptors/metabolism , Estrogen Receptor alpha/metabolism , Female , Humans , Mice , Mice, Nude , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-met/metabolism , Receptor, ErbB-2/metabolism , Receptor, ErbB-3/metabolism , Receptors, Growth Factor/metabolism , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
3.
Mol Cancer Ther ; 8(12): 3296-306, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19952121

ABSTRACT

CUDC-305 is a heat shock protein 90 (HSP90) inhibitor of the novel imidazopyridine class. Here, we report its activities in non-small cell lung cancer (NSCLC) cell lines with gene deregulations conferring primary or secondary resistance to epidermal growth factor receptor (EGFR) inhibitors. We show that CUDC-305 binds strongly to HSP90 extracted from erlotinib-resistant NSCLC cells (IC50 70 nmol/L). This result correlates well with the potent antiproliferative activity in erlotinib-resistant NSCLC cell lines (IC50 120-700 nmol/L) reported previously. Furthermore, it exhibits durable inhibition of multiple oncoproteins and induction of apoptosis in erlotinib-resistant NSCLC cells. CUDC-305 potently inhibits tumor growth in subcutaneous xenograft models of H1975 and A549, which harbor EGFR T790M mutation or K-ras mutations conferring acquired and primary erlotinib resistance, respectively. In addition, CUDC-305 significantly prolongs animal survival in orthotopic lung tumor models of H1975 and A549, which may be partially attributed to its preferential exposure in lung tissue. Furthermore, CUDC-305 is able to extend animal survival in a brain metastatic model of H1975, further confirming its ability to cross the blood-brain barrier. Correlating with its effects in various tumor models, CUDC-305 induces degradation of receptor tyrosine kinases and downstream signaling molecules of the PI3K/AKT and RAF/MEK/ERK pathways simultaneously, with concurrent induction of apoptosis in vivo. In a combination study, CUDC-305 enhanced the antitumor activity of a standard-of-care agent in the H1975 tumor model. These results suggest that CUDC-305 holds promise for the treatment of NSCLC with primary or acquired resistance to EGFR inhibitor therapy.


Subject(s)
Benzodioxoles/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Imidazoles/pharmacology , Lung Neoplasms/drug therapy , Animals , Apoptosis/drug effects , Benzodioxoles/metabolism , Benzodioxoles/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/drug effects , Drug Synergism , Erlotinib Hydrochloride , Female , HSP90 Heat-Shock Proteins/metabolism , Humans , Imidazoles/metabolism , Imidazoles/pharmacokinetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Nude , Mitogen-Activated Protein Kinases/metabolism , Paclitaxel/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Quinazolines/pharmacology , Signal Transduction/drug effects , Survival Analysis , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
4.
Am J Pathol ; 164(5): 1727-37, 2004 May.
Article in English | MEDLINE | ID: mdl-15111319

ABSTRACT

Phosphorylation of proteins on serine or threonine residues preceding proline (pSer/Thr-Pro) is a major regulatory mechanism in cell proliferation and transformation. Interestingly, the pSer/Thr-Pro motifs in proteins exist in two distinct cis and trans conformations, whose conversion rate is normally reduced on phosphorylation, but is catalyzed specifically by the prolyl isomerase Pin1. Pin1 can catalytically induce conformational changes in proteins after phosphorylation, thereby having profound effects on catalytic activity, dephosphorylation, protein-protein interactions, subcellular location, and/or turnover of certain phosphorylated proteins. Recently, it has been shown that Pin1 is overexpressed in human breast cancer cell lines and cancer tissues and plays a critical role in the transformation of mammary epithelial cells by activating multiple oncogenic pathways. Furthermore, Pin1 expression is an excellent independent prognostic marker in prostate cancer. However, little is known about Pin1 expression in other human normal and cancerous tissues. In the present study, we quantified Pin1 expression in 2041 human tumor samples and 609 normal tissue samples as well as normal and transformed human cell lines. We found that Pin1 was usually expressed at very low levels in most normal tissues and its expression was normally associated with cell proliferation, with high Pin1 levels being found only in a few cell types. However, Pin1 was strikingly overexpressed in many different human cancers. Most tumors (38 of 60 tumor types) have Pin1 overexpression in more than 10% of the cases, as compared with the corresponding normal controls, which included prostate, lung, ovary, cervical, brain tumors, and melanoma. Consistent with these findings, Pin1 expression in human cancer cell lines was also higher than that in the normal cell lines examined. These results indicate that Pin1 overexpression is a prevalent and specific event in human cancers. Given previous findings that Pin1 expression is an excellent prognostic marker in prostate cancer and that inhibition of Pin1 can suppress transformed phenotypes and inhibit tumor cell growth, these findings may have important implications for the pathogenesis, diagnosis, and treatment of human cancers.


Subject(s)
Neoplasms/enzymology , Peptidylprolyl Isomerase/biosynthesis , Amino Acid Motifs , Breast Neoplasms/metabolism , Catalysis , Cell Division , Cell Line, Transformed , Cell Line, Tumor , Humans , Immunoblotting , Immunohistochemistry , NIMA-Interacting Peptidylprolyl Isomerase , Phenotype , Phosphorylation , Prognosis , Protein Conformation
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