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Your search keyword '"Atadja, P."' showing total 7 results
Start Over Author "Atadja, P." Journal journal of medicinal chemistry
7 results on '"Atadja, P."'

2. Conformational Refinement of Hydroxamate-Based Histone Deacetylase Inhibitors and Exploration of 3-Piperidin-3-ylindole Analogues of Dacinostat (LAQ824).

Author

Cho, Young Shin, Whitehead, Lewis, Li, Jianke, Chen, Christine H.-T., Jiang, Lei, Vögtle, Markus, Francotte, Eric, Richert, Paul, Wagner, Trixie, Traebert, Martin, Lu, Qiang, Cao, Xueying, Dumotier, Berengere, Fejzo, Jasna, Rajan, Srinivasan, Wang, Ping, Yan-Neale, Yan, Shao, Wenlin, Atadja, Peter, and Shultz, Michael

Published
2010
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3. Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies

Author

Huang, Ying, Sendzik, Martin, Zhang, Jeff, Gao, Zhenting, Sun, Yongfeng, Wang, Long, Gu, Justin, Zhao, Kehao, Yu, Zhengtian, Zhang, Lijun, Zhang, Qiong, Blanz, Joachim, Chen, Zijun, Dubost, Valérie, Fang, Douglas, Feng, Lijian, Fu, Xingnian, Kiffe, Michael, Li, Ling, Luo, Fangjun, Luo, Xiao, Mi, Yuan, Mistry, Prakash, Pearson, David, Piaia, Alessandro, Scheufler, Clemens, Terranova, Remi, Weiss, Andreas, Zeng, Jue, Zhang, Hailong, Zhang, Jiangwei, Zhao, Mengxi, Dillon, Michael P., Jeay, Sebastien, Qi, Wei, Moggs, Jonathan, Pissot-Soldermann, Carole, Li, En, Atadja, Peter, Lingel, Andreas, and Oyang, Counde

Abstract

Polycomb Repressive Complex 2 (PRC2) plays an important role in transcriptional regulation during animal development and in cell differentiation, and alteration of PRC2 activity has been associated with cancer. On a molecular level, PRC2 catalyzes methylation of histone H3 lysine 27 (H3K27), resulting in mono-, di-, or trimethylated forms of H3K27, of which the trimethylated form H3K27me3 leads to transcriptional repression of polycomb target genes. Previously, we have shown that binding of the low-molecular-weight compound EED226 to the H3K27me3 binding pocket of the regulatory subunit EED can effectively inhibit PRC2 activity in cells and reduce tumor growth in mouse xenograft models. Here, we report the stepwise optimization of the tool compound EED226 toward the potent and selective EED inhibitor MAK683 (compound 22) and its subsequent preclinical characterization. Based on a balanced PK/PD profile, efficacy, and mitigated risk of forming reactive metabolites, MAK683 has been selected for clinical development.

Published
2022
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4. N-Hydroxy-3-phenyl-2-propenamides as Novel Inhibitors of Human Histone Deacetylase with in Vivo Antitumor Activity:  Discovery of (2E)-N-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (NVP-LAQ824)

Author

Remiszewski, S. W., Sambucetti, L. C., Bair, K. W., Bontempo, J., Cesarz, D., Chandramouli, N., Chen, R., Cheung, M., Cornell-Kennon, S., Dean, K., Diamantidis, G., France, D., Green, M. A., Howell, K. L., Kashi, R., Kwon, P., Lassota, P., Martin, M. S., Mou, Y., Perez, L. B., Sharma, S., Smith, T., Sorensen, E., Taplin, F., Trogani, N., Versace, R., Walker, H., Weltchek-Engler, S., Wood, A., Wu, A., and Atadja, P.

Abstract

A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC50s < 400 nM in a partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines. Selected compounds having cellular IC50 < 750 nM were tested for maximum tolerated dose (MTD) and for efficacy in the HCT116 human colon tumor xenograft assay. Four compounds having an MTD ≥ 100 mg/kg were selected for dose−response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.

Published
2003

5. Inhibitors of Human Histone Deacetylase:  Synthesis and Enzyme and Cellular Activity of Straight Chain Hydroxamates

Author

Remiszewski, S. W., Sambucetti, L. C., Atadja, P., Bair, K. W., Cornell, W. D., Green, M. A., Howell, K. L., Jung, M., Kwon, P., Trogani, N., and Walker, H.

Abstract

Inhibitors of histone deacetylase (HDAC) have been shown to induce terminal differentiation of human tumor cell lines and to have antitumor effects in vivo. We have prepared analogues of suberoylanilide hydroxamic acid (SAHA) and trichostatin A and have evaluated them in a human HDAC enzyme inhibition assay, a p21waf1 (p21) promoter assay, and in monolayer growth inhibition assays. One compound, 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-benzamide, was found to affect the growth of a panel of eight human tumor cell lines differentially.

Published
2002
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6. Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy.

Author

Huang Y, Zhang J, Yu Z, Zhang H, Wang Y, Lingel A, Qi W, Gu J, Zhao K, Shultz MD, Wang L, Fu X, Sun Y, Zhang Q, Jiang X, Zhang J, Zhang C, Li L, Zeng J, Feng L, Zhang C, Liu Y, Zhang M, Zhang L, Zhao M, Gao Z, Liu X, Fang D, Guo H, Mi Y, Gabriel T, Dillon MP, Atadja P, and Oyang C

Subjects
Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, Cell Proliferation drug effects, Crystallography, X-Ray, Dogs, Female, Haplorhini, Histones metabolism, Humans, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse metabolism, Lysine metabolism, Male, Methylation drug effects, Mice, Mice, Inbred BALB C, Mice, Nude, Molecular Docking Simulation, Polycomb Repressive Complex 2 chemistry, Polycomb Repressive Complex 2 metabolism, Rats, Sulfones pharmacokinetics, Sulfones therapeutic use, Triazoles pharmacokinetics, Triazoles therapeutic use, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Polycomb Repressive Complex 2 antagonists & inhibitors, Sulfones chemistry, Sulfones pharmacology, Triazoles chemistry, Triazoles pharmacology
Abstract

Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective, and orally bioavailable EED inhibitor compound 43 (EED226). Guided by X-ray crystallography, compound 43 was discovered by fragmentation and regrowth of compound 7, a PRC2 HTS hit that directly binds EED. The ensuing scaffold hopping followed by multiparameter optimization led to the discovery of 43. Compound 43 induces robust and sustained tumor regression in EZH2 MUT preclinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anticancer strategy.

Published
2017
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7. Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors.

Author

Shultz MD, Cao X, Chen CH, Cho YS, Davis NR, Eckman J, Fan J, Fekete A, Firestone B, Flynn J, Green J, Growney JD, Holmqvist M, Hsu M, Jansson D, Jiang L, Kwon P, Liu G, Lombardo F, Lu Q, Majumdar D, Meta C, Perez L, Pu M, Ramsey T, Remiszewski S, Skolnik S, Traebert M, Urban L, Uttamsingh V, Wang P, Whitebread S, Whitehead L, Yan-Neale Y, Yao YM, Zhou L, and Atadja P

Subjects
Acrylamides chemical synthesis, Acrylamides pharmacology, Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Drug Screening Assays, Antitumor, ERG1 Potassium Channel, HCT116 Cells, Half-Life, Histone Deacetylase Inhibitors chemical synthesis, Histone Deacetylase Inhibitors pharmacology, Humans, Hydroxamic Acids chemical synthesis, Hydroxamic Acids pharmacology, In Vitro Techniques, Mice, Mice, Nude, Microsomes, Liver metabolism, Models, Molecular, Neoplasm Transplantation, Patch-Clamp Techniques, Radioligand Assay, Rats, Rats, Sprague-Dawley, Stereoisomerism, Structure-Activity Relationship, Tissue Distribution, Transplantation, Heterologous, Acrylamides toxicity, Antineoplastic Agents toxicity, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Histone Deacetylase Inhibitors toxicity, Hydroxamic Acids toxicity
Abstract

Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.

Published
2011
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