Abstract

Receptor tyrosine kinases (RTKs) utilize ATP to autophosphorylate specific tyrosine residues in the sequence of proteins. A variety of tumors have dysfunctional RTKs, often overexpressed, and result in inappropriate signaling. Thus inhibition of RTKs have provided a new paradigm for cancer chemotherapy and several RTK inhibitors are currently in clinical trials as antitumor agents. We recently discovered a series of novel RTK inhibitors which have exceptional single, dual and multi-inhibitory effects against RTKs. In addition, we also discovered a separate series of novel analogs which possess potent RTK inhibitory activity, antiangiogenic activity along with dihydrofolate reductase (DHFR) inhibitory activity in single agents. On the basis of our preliminary studies, we propose to carry out a structure optimization of our lead analogs to afford the most effective agents and to provide a structure-activity relationship study (SAR).
The specific aims are to synthesize compounds to optimize inhibitory activity against vascular endothelial growth factor receptor-2 (VEGFR-2), against endothelial growth factor receptor (EGFR), against platelet-derived growth factor receptor-beta (PDGFR-beta). To synthesize analogs to optimize DHFR and VEGFR-2 inhibitory activity in single agents. Since some of the lead analogs have multiple inhibitory effects against more than one RTK, the SAR generated in these studies will also allow a delineation of structural requirements necessary for single or multiple inhibitory activity against RTKs. All of the compounds will be evaluated on a collaborative basis for in vitro inhibitory activity against VEGFR-2, EGFR, PDGFR-beta, FGFR and the CAM assay for antiangiogenic activity (Dr. Michael Ihnat) and appropriate analogs against DHFR (Dr. Roy L. Kisliuk). Appropriate analogs will also be evaluated against A431 cells that overexpress EGFR (Dr. Ihnat). In addition, we have selected three analogs from our preliminary studies for in vivo assay in the B16 mouse melanoma tumor model for antitumor activity. At least four additional analogs from this study will be selected for in vivo evaluation (Dr. Michael Ihnat). This study should provide structurally optimized analogs which function as single, dual or multitargeted inhibitors of RTKs as well as analogs for VEGFR-2 and DHFR as antitumor agents with a different spectrum of antitumor activity and perhaps afford analogs that can be advanced to clinical trials against solid tumors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098850-04
Application #
6998979
Study Section
Special Emphasis Panel (ZRG1-ET-2 (02))
Program Officer
Fu, Yali
Project Start
2003-01-20
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
4
Fiscal Year
2006
Total Cost
$286,901
Indirect Cost

  Institution

Name
Duquesne University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004501193
City
Pittsburgh
State
PA
Country
United States
Zip Code
15282

  Publications

Queener, S F; Cody, V; Pace, J et al. (2013) Trimethoprim resistance of dihydrofolate reductase variants from clinical isolates of Pneumocystis jirovecii. Antimicrob Agents Chemother 57:4990-8
Cody, Vivian; Pace, Jim; Queener, Sherry F et al. (2013) Kinetic and structural analysis for potent antifolate inhibition of Pneumocystis jirovecii, Pneumocystis carinii, and human dihydrofolate reductases and their active-site variants. Antimicrob Agents Chemother 57:2669-77
Gangjee, Aleem; Namjoshi, Ojas A; Yu, Jianming et al. (2013) N2-Trimethylacetyl substituted and unsubstituted-N4-phenylsubstituted-6-(2-pyridin-2-ylethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines: design, cellular receptor tyrosine kinase inhibitory activities and in vivo evaluation as antiangiogenic, antimetastati Bioorg Med Chem 21:1312-23
Gangjee, Aleem; Zaware, Nilesh; Raghavan, Sudhir et al. (2013) Synthesis and biological activity of 5-chloro-N?-substituted phenyl-9H-pyrimido[4,5-b]indole-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic agents. Bioorg Med Chem 21:1857-64
Gangjee, Aleem; Zhao, Ying; Ihnat, Michael A et al. (2012) Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents. Bioorg Med Chem 20:4217-25
Gangjee, Aleem; Zaware, Nilesh; Raghavan, Sudhir et al. (2012) Nýýý-(3-Bromophenyl)-7-(substituted benzyl) pyrrolo[2,3-d]pyrimidines as potent multiple receptor tyrosine kinase inhibitors: design, synthesis, and in vivo evaluation. Bioorg Med Chem 20:2444-54
Gangjee, Aleem; Kurup, Sonali; Ihnat, Michael A et al. (2012) N?-Aryl-6-substitutedphenylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as receptor tyrosine kinase inhibitors. Bioorg Med Chem 20:910-4
Gangjee, Aleem; Namjoshi, Ojas A; Keller, Staci N et al. (2011) 2-Amino-4-methyl-5-phenylethyl substituted-7-N-benzyl-pyrrolo[2,3-d]pyrimidines as novel antitumor antimitotic agents that also reverse tumor resistance. Bioorg Med Chem 19:4355-65
Gangjee, Aleem; Lin, Xin; Biondo, Lisa R et al. (2010) CoMFA analysis of tgDHFR and rlDHFR based on antifolates with 6-5 fused ring system using the all-orientation search (AOS) routine and a modified cross-validated r(2)-guided region selection (q(2)-GRS) routine and its initial application. Bioorg Med Chem 18:1684-701
Gangjee, Aleem; Kurup, Sonali; Ihnat, Michael A et al. (2010) Synthesis and biological activity of N(4)-phenylsubstituted-6-(2,4-dichloro phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic and antitumor agents. Bioorg Med Chem 18:3575-87

Showing the most recent 10 out of 19 publications