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Cudc-101

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https://www.readbyqxmd.com/read/27903123/drug-priming-enhances-radiosensitivity-of-adamantinomatous-craniopharyngioma-via-downregulation-of-survivin
#1
Christina Stache, Christiane Bils, Rudolf Fahlbusch, Jörg Flitsch, Michael Buchfelder, Harald Stefanits, Thomas Czech, Udo Gaipl, Benjamin Frey, Rolf Buslei, Annett Hölsken
OBJECTIVE In this study, the authors investigated the underlying mechanisms responsible for high tumor recurrence rates of adamantinomatous craniopharyngioma (ACP) after radiotherapy and developed new targeted treatment protocols to minimize recurrence. ACPs are characterized by the activation of the receptor tyrosine kinase epidermal growth factor receptor (EGFR), known to mediate radioresistance in various tumor entities. The impact of tyrosine kinase inhibitors (TKIs) gefitinib or CUDC-101 on radiation-induced cell death and associated regulation of survivin gene expression was evaluated...
December 2016: Neurosurgical Focus
https://www.readbyqxmd.com/read/26957440/cudc-101-a-novel-inhibitor-of-full-length-androgen-receptor-flar-and-androgen-receptor-variant-7-ar-v7-activity-mechanism-of-action-and-in-vivo-efficacy
#2
Huiying Sun, Sanjay N Mediwala, Adam T Szafran, Michael A Mancini, Marco Marcelli
Castration-resistant prostate cancer (CRPC) is an androgen receptor (AR)-dependent disease expected to cause the death of more than 27,000 Americans in 2015. There are only a few available treatments for CRPC, making the discovery of new drugs an urgent need. We report that CUDC-101 (an inhibitor od HER2/NEU, EGFR and HDAC) inhibits both the full length AR (flAR) and the AR variant AR-V7. This observation prompted experiments to discover which of the known activities of CUDC-101 is responsible for the inhibition of flAR/AR-V7 signaling...
June 2016: Hormones & Cancer
https://www.readbyqxmd.com/read/26934320/carfilzomib-potentiates-cudc-101-induced-apoptosis-in-anaplastic-thyroid-cancer
#3
Lisa Zhang, Myriem Boufraqech, Ross Lake, Electron Kebebew
Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, with no effective treatment currently available. Previously, we identified agents active against ATC cells, both in vitro and in vivo, using quantitative high-throughput screening of 3282 clinically approved drugs and small molecules. Here, we report that combining two of these active agents, carfilzomib, a second-generation proteasome inhibitor, and CUDC-101, a histone deacetylase and multi-kinase inhibitor, results in increased, synergistic activity in ATC cells...
March 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/26032687/histone-deacetylase-inhibitors-resensitize-egfr-egfrviii-overexpressing-erlotinib-resistant-glioblastoma-cells-to-tyrosine-kinase-inhibition
#4
Katrin Liffers, Katarina Kolbe, Manfred Westphal, Katrin Lamszus, Alexander Schulte
Although the epidermal growth factor receptor (EGFR) is overexpressed and/or amplified in more than 50 % of all glioblastomas (GBM), therapeutic targeting of the EGFR has not yet been successful. Since histone deacetylases (HDAC) have been described as controlling EGFR expression, we combined the EGFR tyrosine kinase inhibitor erlotinib with different HDAC inhibitors (HDACi) and investigated the benefit of combinatorial therapy for glioblastoma cells. Using representative models of EGFR-amplified, erlotinib-sensitive and -resistant GBM with or without EGFRvIII expression, we determined proliferation, migration, and EGFR-dependent signaling in response to erlotinib and HDACi alone or in combination...
February 2016: Targeted Oncology
https://www.readbyqxmd.com/read/25940539/dual-inhibition-of-hdac-and-egfr-signaling-with-cudc-101-induces-potent-suppression-of-tumor-growth-and-metastasis-in-anaplastic-thyroid-cancer
#5
COMPARATIVE STUDY
Lisa Zhang, Yaqin Zhang, Amit Mehta, Myriem Boufraqech, Sean Davis, Jing Wang, Ze Tian, Zhiya Yu, Matthew B Boxer, Jeffrey A Kiefer, John A Copland, Robert C Smallridge, Zhuyin Li, Min Shen, Electron Kebebew
Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies that currently has no effective therapy. We performed quantitative high-throughput screening (qHTS) in three ATC cell lines using 3,282 clinically approved drugs and drug candidates, and identified 100 active agents. Enrichment analysis of active compounds showed that inhibitors of EGFR and histone deacetylase (HDAC) were most active. Of these, the first-in-class dual inhibitor of EGFR, HER2 and HDACs, CUDC-101, had the highest efficacy and lower IC50 than established drugs...
April 20, 2015: Oncotarget
https://www.readbyqxmd.com/read/25929339/dual-inhibition-of-hdac-and-egfr-signaling-with-cudc-101-induces-potent-suppression-of-tumor-growth-and-metastasis-in-anaplastic-thyroid-cancer
#6
Lisa Zhang, Yaqin Zhang, Amit Mehta, Myriem Boufraqech, Sean Davis, Jing Wang, Ze Tian, Zhiya Yu, Matthew B Boxer, Jeffrey A Kiefer, John A Copland, Robert C Smallridge, Zhuyin Li, Min Shen, Electron Kebebew
Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies that currently has no effective therapy. We performed quantitative high-throughput screening (qHTS) in three ATC cell lines using 3,282 clinically approved drugs and drug candidates, and identified 100 active agents. Enrichment analysis of active compounds showed that inhibitors of EGFR and histone deacetylase (HDAC) were most active. Of these, the first-in-class dual inhibitor of EGFR, HER2 and HDACs, CUDC-101, had the highest efficacy and lower IC50 than established drugs...
April 13, 2015: Oncotarget
https://www.readbyqxmd.com/read/25573383/a-phase-i-study-of-cudc-101-a-multitarget-inhibitor-of-hdacs-egfr-and-her2-in-combination-with-chemoradiation-in-patients-with-head-and-neck-squamous-cell-carcinoma
#7
MULTICENTER STUDY
Thomas J Galloway, Lori J Wirth, Alexander D Colevas, Jill Gilbert, Julie E Bauman, Nabil F Saba, David Raben, Ranee Mehra, Anna W Ma, Ruzanna Atoyan, Jing Wang, Barbara Burtness, Antonio Jimeno
PURPOSE: CUDC-101 is a small molecule that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HDAC) with preclinical activity in head and neck squamous cell cancer (HNSCC). The primary objective of this investigation is to determine the maximum tolerated dose (MTD) of CUDC-101 with cisplatin-radiotherapy in the treatment of HNSCC. EXPERIMENTAL DESIGN: CUDC-101 monotherapy was administered intravenously three times weekly (Monday, Wednesday, Friday) for a one-week run-in, then continued with concurrent cisplatin (100 mg/m(2) every 3 weeks) and external beam radiation (70 Gy to gross disease) over 7 weeks...
April 1, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/25450670/human-atp-binding-cassette-transporters-abcb1-and-abcg2-confer-resistance-to-cudc-101-a-multi-acting-inhibitor-of-histone-deacetylase-epidermal-growth-factor-receptor-and-human-epidermal-growth-factor-receptor-2
#8
Chung-Pu Wu, Sung-Han Hsiao, Ching-Ya Su, Shi-Yu Luo, Yan-Qing Li, Yang-Hui Huang, Chia-Hung Hsieh, Chiun-Wei Huang
CUDC-101 is the first small-molecule inhibitor designed to simultaneously inhibit epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2) and histone deacetylase (HDAC) in cancer cells. Recently, in its first in human phase I study, CUDC-101 showed promising single agent activity against advanced solid tumors and favorable pharmacodynamic profile. However, the risk of developing drug resistance to CUDC-101 can still present a significant therapeutic challenge to clinicians in the future...
December 15, 2014: Biochemical Pharmacology
https://www.readbyqxmd.com/read/25107918/phase-i-first-in-human-study-of-cudc-101-a-multitargeted-inhibitor-of-hdacs-egfr-and-her2-in-patients-with-advanced-solid-tumors
#9
Toshio Shimizu, Patricia M LoRusso, Kyri P Papadopoulos, Amita Patnaik, Muralidhar Beeram, Lon S Smith, Drew W Rasco, Theresa A Mays, Glenda Chambers, Anna Ma, Jing Wang, Robert Laliberte, Maurizio Voi, Anthony W Tolcher
PURPOSE: This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-hour intravenous (i.v.) infusion for 5 consecutive days every 2 weeks. EXPERIMENTAL DESIGN: Twenty-five patients with advanced solid tumors received escalating doses of CUDC-101 (range, 75-300 mg/m(2)/day) following a standard 3 + 3 dose escalation design. RESULTS: The MTD was determined to be 275 mg/m(2)...
October 1, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/24900760/novel-64-cu-labeled-cudc-101-for-in-vivo-pet-imaging-of-histone-deacetylases
#10
Qingqing Meng, Feng Li, Sheng Jiang, Zheng Li
We report the design, synthesis, and biological evaluation of a (64)Cu-labeled histone deacetylase (HDAC) imaging probe, which was obtained by introduction of metal chelator through click reaction of HDAC inhibitor CUDC-101 and then radiolabeled with (64)Cu. The resulting (64)Cu-labeled compound 7 ([(64)Cu]7) was identified as a positron emission tomography (PET) imaging probe to noninvasively visualize HDAC expression in vivo. Cell based competitive assay established the specific binding of [(64)Cu]7 to HDACs...
September 12, 2013: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/24366214/determination-of-cudc-101-in-rat-plasma-by-liquid-chromatography-mass-spectrometry-and-its-application-to-a-pharmacokinetic-study
#11
Qingwei Zhang, Congcong Wen, Zheng Xiang, Jianshe Ma, Xianqin Wang
CUDC-101 is a multi-targeted, small-molecule inhibitor of histone deacetylase (HDAC), epidermal growth factor receptor tyrosine kinase (EGFR/ErbB1), and human epidermal growth factor receptor 2 tyrosine kinase (HER2/neu or ErbB2) with potential antineoplastic activity. A sensitive and selective liquid chromatography mass spectrometry method for determination of CUDC-101 in rat plasma was developed. After addition of carbamazepine as internal standard (IS), protein precipitation by acetonitrile-methanol (9:1, v/v) was used as sample preparation...
March 2014: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/24342668/cudc-101-a-histone-deacetylase-inhibitor-improves-the-in-vitro-and-in-vivo-developmental-competence-of-somatic-cell-nuclear-transfer-pig-embryos
#12
Jun-Xue Jin, Suo Li, Yu Hong, Long Jin, Hai-Ying Zhu, Qing Guo, Qing-Shan Gao, Chang-Guo Yan, Jin-Dan Kang, Xi-Jun Yin
The aim of the present study was to examine the effects of CUDC-101, a novel histone deacetylase inhibitor, on the in vitro development and expression of the epigenetic marker histone H3 at lysine 9 (AcH3K9) in pig SCNT embryos. We found that treatment with 1 μmol/L CUDC-101 for 24 hours significantly improved the development of pig SCNT embryos. Compared with the control group, the blastocyst rate was higher (18.5% vs. 10.3%; P < 0.05). To assess in vivo developmental potency, CUDC-101-treated SCNT embryos were transferred into two surrogate mothers, resulting in one pregnancy with six fetuses...
March 1, 2014: Theriogenology
https://www.readbyqxmd.com/read/24216225/current-challenges-and-clinical-investigations-of-epidermal-growth-factor-receptor-egfr-and-erbb-family-targeted-agents-in-the-treatment-of-head-and-neck-squamous-cell-carcinoma-hnscc
#13
REVIEW
Roger B Cohen
Overexpression of the epidermal growth factor receptor (EGFR) is a common characteristic of head and neck squamous cell carcinomas (HNSCC). Cetuximab is a chimeric anti-EGFR monoclonal antibody (mAb) with multiple approved indications in HNSCC, including with radiation therapy (RT) for locoregionally advanced disease, as monotherapy after platinum progression, and with platinum/5-fluorouracil for recurrent or metastatic disease. There remain, however, numerous unanswered questions regarding the optimal use of cetuximab in HNSCC, including patient selection, its mechanisms of action and resistance, the effect of human papillomavirus status on outcomes, its role when combined with induction chemotherapy or adjuvant radiation, and optimal management of skin toxicity and hypersensitivity reactions...
May 2014: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/23895688/a-structural-insight-into-hydroxamic-acid-based-histone-deacetylase-inhibitors-for-the-presence-of-anticancer-activity
#14
H Rajak, A Singh, K Raghuwanshi, R Kumar, P K Dewangan, R Veerasamy, P C Sharma, A Dixit, P Mishra
Histone deacetylase inhibitors (HDACi) have been actively explored as anti-cancer agents due to their ability to prevent deacetylation of histones, resulting in uncoiling of chromatin and stimulation of a range of genes associated in the regulation of cell survival, proliferation, differentiation and apoptosis. During the past several years, many HDACi have entered pre-clinical or clinical research as anti-cancer agents with satisfying results. Out of these, more than 8 novel hydroxamic acid based HDACi i.e...
2014: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/23536719/potential-advantages-of-cudc-101-a-multitargeted-hdac-egfr-and-her2-inhibitor-in-treating-drug-resistance-and-preventing-cancer-cell-migration-and-invasion
#15
Jing Wang, Natalie W Pursell, Maria Elena S Samson, Ruzanna Atoyan, Anna W Ma, Abdelkader Selmi, Wanlu Xu, Xiong Cai, Maurizio Voi, Pierre Savagner, Cheng-Jung Lai
CUDC-101 is a novel, small-molecule, anticancer agent targeting histone deacetylase (HDAC), EGF receptor (EGFR), and HER2. It is currently in phase I clinical development in patients with solid tumors. Previously, we reported that CUDC-101 has potent antiproliferative and proapoptotic activity in cultured tumor cells and in vivo xenograft models. We now show that cancer cells that have acquired resistance to single-target EGFR inhibitors through upregulation of AXL or loss of E-cadherin remain sensitive to CUDC-101, which inhibits MET- and AXL-mediated signaling, restores E-cadherin expression, and reduces cell migration...
June 2013: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/22370774/multi-targeted-hybrids-based-on-hdac-inhibitors-for-anti-cancer-drug-discovery
#16
Seung-Yong Seo
Multi-targeted hybrids combine two drugs in a single molecule to have greater medicinal effects than its individual components. Recently, a number of anti-cancer drug candidates such as CUDC-101 (Curis) have been designed based on linking properly two selected pharmacophores endowed with activity against different therapeutic targets.
February 2012: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/20388807/cudc-101-a-multitargeted-inhibitor-of-histone-deacetylase-epidermal-growth-factor-receptor-and-human-epidermal-growth-factor-receptor-2-exerts-potent-anticancer-activity
#17
Cheng-Jung Lai, Rudi Bao, Xu Tao, Jing Wang, Ruzanna Atoyan, Hui Qu, Da-Gong Wang, Ling Yin, Maria Samson, Jeffrey Forrester, Brian Zifcak, Guang-Xin Xu, Steven DellaRocca, Hai-Xiao Zhai, Xiong Cai, William E Munger, Mitchell Keegan, Carmen V Pepicelli, Changgeng Qian
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...
May 1, 2010: Cancer Research
https://www.readbyqxmd.com/read/20143778/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
#18
Xiong Cai, Hai-Xiao Zhai, Jing Wang, Jeffrey Forrester, Hui Qu, Ling Yin, Cheng-Jung Lai, Rudi Bao, Changgeng Qian
By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4...
March 11, 2010: Journal of Medicinal Chemistry
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