Evaluation of novel cell cycle inhibitors in mantle cell lymphoma

Park, I.-W.; Reddy, M. V. Ramana; Reddy, E. Premkumar; Groopman, Jerome E.

doi:10.1038/sj.onc.1210350

Cited by 17 publications

(9 citation statements)

References 34 publications

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“…In vitro studies with 28 showed that incubation of human leukemic cells with this compound results in the inhibition of PI3K/AKT pathway, down regulation of cyclin D1, induction of NOXA and BIM and activation of JNK pathway. 6 Treatment of MDS patients with 28 results in a dramatic reduction of cytogenetically abnormal cells with a minimal inhibition of normal hematopoiesis. This drug is currently in Phase III clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Clinical Stage Multi-Kinase Inhibitor Sodium (E)-2-{2-Methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): Synthesis, Structure–Activity Relationship, and Biological Activity

et al. 2011

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Cyclin D proteins are elevated in many cancer cells and targeted deletion of Cyclin D1 gene in the mammary tissues protects mice from breast cancer. Accordingly, there is an increasing awareness of this novel non-enzymatic target for cancer therapeutics. We have developed novel, non-alkylating styryl benzyl sulfones that induce cell death in wide variety of cancer cells without affecting the proliferation and survival of normal cells. The development of derivatized Styryl Benzyl Sulfones followed logically from a tumor cell cytotoxicity screen performed in our laboratory that did not have an a priori target profile. Modifications of some of the precursor molecules led to lead optimization with regard to tumor cell cytotoxicity. In this report we describe the synthesis and structure-activity relationships of novel, non-alkylating (E) styryl benzyl sulfones, and the development of the novel anti-cancer agent sodium (E)-2-{2-methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl]phenylamino}-acetate (ON 01910.Na), which is in Phase III trials for myelodysplastic syndromes (MDS) associated with aberrant expression of cyclin D proteins.

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Section: Introductionmentioning

confidence: 99%

Discovery of a Clinical Stage Multi-Kinase Inhibitor Sodium (E)-2-{2-Methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): Synthesis, Structure–Activity Relationship, and Biological Activity

et al. 2011

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“…Recent studies with 6s, 6aa, and 6ab show that these compounds altered the growth and cell cycle status of mantle cell lymphoma cell lines and potently inhibited the expression of several important proteins, including cyclin-dependent kinase 19,20 4, p53, mouse double minute 2 (MDM2), and cyclin D. 23 Since 6s, 6aa, and 6ab are highly effective in various combinations with conventional chemotherapy, 23 the lack of overt hematotoxicity of these compounds may be beneficial for testing novel combinations for advanced cancers, including tumors resistant to conventional chemotherapy. In addition, their safety profile seen with normal hematopoietic cells suggests that these compounds have a potential use in in vitro purging of tumor cells from patient bone marrow for use in autologous bone marrow transplantation.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of (E)-Styrylbenzylsulfones as Novel Anticancer Agents

et al. 2007

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Cell cycle progression is regulated by cyclins and cyclin-dependent kinases, which are formed at specific stages of the cell cycle and regulate the G1/S and G2/M phase transitions, employing a series of "checkpoints" governed by phosphorylation of their substrates. Tumor development is associated with the loss of these checkpoint controls, and this provides an approach for the development of therapeutic agents that can specifically target tumor cells. Here, we describe the synthesis and SAR of a novel group of cytotoxic molecules that selectively induce growth arrest of normal cells in the G1 phase while inducing a mitotic arrest of tumor cells resulting in selective killing of tumor cell populations with little or no effect on normal cell viability. The broad spectrum of antitumor activity in vitro and xenograft models, lack of in vivo toxicity, and drug resistance suggest potential for use of these agents in cancer therapy.

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“…1A) [1]. While the drug has little or no effect on normal cell viability, it induces apoptosis, and has activity against most human cancer cell lines in vitro (>100 tumor types tested, including drug resistant lines) as well against a broad spectrum of human xenografts in mice [2]. As a potent mitotic inhibitor the drug also inhibits cyclin D1 expression and induces selective G2/M arrest of tumor cells characterized by spindle abnormalities leading to apoptosis [3].…”

Section: Introductionmentioning

confidence: 99%

Determination of the glucuronide metabolite of ON 013100, a benzylstyrylsulfone antineoplastic drug, in colon cancer cells using LC/MS/MS

Cho

Cosenza

Pallela

et al. 2013

Journal of Pharmaceutical and Biomedical Analysis

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ON 013100, (E)-2,4,6-trimethoxystyryl-3-hydroxy-4-methoxybenzyl sulfone, is a potent kinase inhibitor whose phosphate form is in Phase I clinical trials in lymphoma and acute lymphoid leukemia. The objectives were to: (a) investigate the possible presence of the glucuronide metabolite of the drug in two representative colon cancer cell lines, a drug resistant (colo-205) and a drug sensitive (colo-320); (b) quantify the glucuronide metabolite and the unchanged drug in the cells after treatment with ON 013100. The glucuronide was synthesized and a selective LC/MS/MS method was developed and validated for the characterization and quantification of the metabolite. The glucuronide metabolite (570.6 Da) was found in the drug-resistant cells upon a 1 h incubation with ON 013100 (20 μg/ml). After treatment with the drug, the concentration of the metabolite gradually decreased from 0.84 μg/ml at 0 h through 0.21 μg/ml at 6 h to below detection limit of 8.0 ng/ml at 9 h. No glucuronide metabolite was detected in the drug-sensitive cells. The concentrations of intact ON 013100 in the drug-resistant cells gradually decreased from 0.41 μg/ml (0 h) to 0.06 μg/ml (9 h). The corresponding concentrations of the intact drug in the drug-sensitive cells were from 2.88 μg/ml to 0.94 μg/ml.

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Evaluation of novel cell cycle inhibitors in mantle cell lymphoma

Cited by 17 publications

References 34 publications

Discovery of a Clinical Stage Multi-Kinase Inhibitor Sodium (E)-2-{2-Methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): Synthesis, Structure–Activity Relationship, and Biological Activity

Discovery of a Clinical Stage Multi-Kinase Inhibitor Sodium (E)-2-{2-Methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): Synthesis, Structure–Activity Relationship, and Biological Activity

Design, Synthesis, and Biological Evaluation of (E)-Styrylbenzylsulfones as Novel Anticancer Agents

Determination of the glucuronide metabolite of ON 013100, a benzylstyrylsulfone antineoplastic drug, in colon cancer cells using LC/MS/MS

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