Cell cycle progression is regulated by cyclin-dependent kinases, which are critical for cell growth. Tumor development is often associated with genetic alterations in growth regulatory pathways leading to a loss of checkpoints that promotes cell cycle progression. Most normal cells differ from tumor cells with respect to their G1 checkpoint control, and this difference provides an approach for the development of therapeutic agents that discriminate between normal and tumor cells. In this application, we present data, which show the derivation of a novel group of small molecule kinase inhibitors that induce growth arrest of normal cells in the G1 phase of the cell cycle, while inducing a mitotic arrest of tumor cells. These compounds, termed as ON01 series inhibit the cyclin dependent kinases, CDK2 and CDK1, as well as PDGF Receptor. The ensuing result appears to be selective killing of tumor cell populations with little or no effect on normal cell viability. We propose experiments aimed at delineating their mechanism of action and their value as cancer therapeutics.
The aims are: 1. To determine the kinetics of inhibition of CDK1 and CDK2 by ON01500 and ON013100; 2. To study the mechanism by which ON01 series block normal cell cycle progression in the G1 phase of the cell cycle; 3. To study the molecular consequences of CDK1 inhibition in tumor cells with respect to Survivin and Stathamin, which are known to play a critical role in the spindle assembly; 4. To carry out safety and bioavailability and efficacy studies with two candidate drugs, ON01500- DMG and ON013100-P, using MDR+ and MDR- tumor cell lines; and 5. To determine the in vitro and in vivo effects of ON013100 on hematopoietic cell growth and differentiation and determine whether 13100 can be used as a purging agent for human leukemia's.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109820-02
Application #
6923643
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Arya, Suresh
Project Start
2004-08-01
Project End
2009-05-31
Budget Start
2005-08-24
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$308,525
Indirect Cost
Name
Temple University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Prasad, Anil; Shrivastava, Ashutosh; Papadopoulos, Evangelos et al. (2013) Combined administration of rituximab and on 013105 induces apoptosis in mantle cell lymphoma cells and reduces tumor burden in a mouse model of mantle cell lymphoma. Clin Cancer Res 19:85-95
Reddy, M V Ramana; Akula, Balaiah; Cosenza, Stephen C et al. (2012) (Z)-1-aryl-3-arylamino-2-propen-1-ones, highly active stimulators of tubulin polymerization: synthesis, structure-activity relationship (SAR), tubulin polymerization, and cell growth inhibition studies. J Med Chem 55:5174-87
Nuthalapati, Silpa; Zhou, Qingyu; Guo, Ping et al. (2012) Preclinical pharmacokinetic and pharmacodynamic evaluation of novel anticancer agents, ON01910.Na (Rigosertib, Estybon™) and ON013105, for brain tumor chemotherapy. Pharm Res 29:2499-511
Ellingson, Benjamin M; LaViolette, Peter S; Rand, Scott D et al. (2011) Spatially quantifying microscopic tumor invasion and proliferation using a voxel-wise solution to a glioma growth model and serial diffusion MRI. Magn Reson Med 65:1131-43
Ellingson, Benjamin M; Malkin, Mark G; Rand, Scott D et al. (2011) Volumetric analysis of functional diffusion maps is a predictive imaging biomarker for cytotoxic and anti-angiogenic treatments in malignant gliomas. J Neurooncol 102:95-103
Ellingson, Benjamin M; Cloughesy, Timothy F; Lai, Albert et al. (2011) Graded functional diffusion map-defined characteristics of apparent diffusion coefficients predict overall survival in recurrent glioblastoma treated with bevacizumab. Neuro Oncol 13:1151-61
Reddy, M V Ramana; Venkatapuram, Padmavathi; Mallireddigari, Muralidhar R et al. (2011) 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. J Med Chem 54:6254-76
Reddy, M V Ramana; Pallela, Venkat R; Cosenza, Stephen C et al. (2010) Design, synthesis and evaluation of (E)-alpha-benzylthio chalcones as novel inhibitors of BCR-ABL kinase. Bioorg Med Chem 18:2317-26
Baker, Stacey J; Reddy, E Premkumar (2010) Targeted inhibition of kinases in cancer therapy. Mt Sinai J Med 77:573-86
Ellingson, Benjamin M; Rand, Scott D; Malkin, Mark G et al. (2010) Utility of functional diffusion maps to monitor a patient diagnosed with gliomatosis cerebri. J Neurooncol 97:419-23

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