The location of translation initiation at the apex of many well-defined oncogenic, pro-apoptotic and tumor-suppressor pathways makes it an attractive target for the development of anti-cancer agents and represents a new paradigm in cancer therapy. Because restoration of translational control down-regulates oncogenic proteins with minimal effect on housekeeping proteins, small molecule inhibitors of translation initiation have excellent potential for achieving a wide therapeutic window. The emergence of translation initiation inhibitors as a new class of anticancer drugs is consistent with the current view that modern anti-cancer therapy must be target-specific and inhibit the growth of cancer cells but not of normal cells, a distinct difference from still-prevalent genotoxic therapies. The goal of this proposal is to execute a hit-to-lead optimization of #4EGI-1, a thiazolyl-hydrazone propionic acid (THPA) derivative to obtain a potent and selective preclinical lead candidate. The #4EGI-1, identified in our laboratories by high throughput screening of chemical libraries inhibits eIF4E/eIF4G interaction that is essential for the formation of eIF4F complex (a critical regulatory step in the translation initiation cascade) is an inhibitor of cap-dependent translation. The structure-based optimization will combine insights gained from the NMR- and docking studies that resulted in a model of eIF4E-#4EGI-1 complex, preliminary medicinal chemistry that identified the putative pharmacophore and performed a limited structure-activity relationship studies, a panel of in vitro assays that include: 1. competitive binding to eIF4E, 2. inhibition of cancer cell growth, 3. pull-down experiment to demonstrate disruption of eIF4F complex, and 4. inhibition of cap dependent translation in cell extracts, and a xenograft mouse model of human cancer. Our integrative and iterative strategy will include two tier elaboration of the THPA scaffold. Initially, we will design focused libraries directed toward the substituent at position 3 of the propionic acid, and positions 4 and 5 of the thiazolidine ring aiming to enhance interaction with the hot spot and putative exosites on eIF4E. In addition, we will rigidify the THPA scaffold to lock it in either E or Z configuration around the exocyclic C=N in order to prevent spontaneous isomerization thus characterizing the bioactive configuration. Taken together, our effort will lead to the development of a potent and selective preclinical anti-cancer drug candidate targeting the eIF4F complex. PUBLIC HEALTH REVELANCE: The location of translation initiation at the apex of many well-defined oncogenic, pro-apoptotic and tumor- suppressor pathways makes it an attractive target for the development of anti-cancer agents and represents a new paradigm in cancer therapy. Because restoration of translational control down-regulates oncogenic proteins with minimal effect on housekeeping proteins, small molecule inhibitors of translation initiation have excellent potential for achieving a wide therapeutic window. We plan to carry out a hit-to-lead optimization of #4EGI-1 a small molecule inhibitor of eIF4E/eIF4G interaction, which is a crucial player in the translation initiation cascade, in an effort to identify a potent and selective preclinical candidate.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121357-05
Application #
8212468
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
2008-04-01
Project End
2012-06-30
Budget Start
2012-02-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$184,779
Indirect Cost
$75,765
Name
Harvard University
Department
None
Type
Organized Research Units
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Mahalingam, Poornachandran; Takrouri, Khuloud; Chen, Ting et al. (2014) Synthesis of rigidified eIF4E/eIF4G inhibitor-1 (4EGI-1) mimetic and their in vitro characterization as inhibitors of protein-protein interaction. J Med Chem 57:5094-111
Papadopoulos, Evangelos; Jenni, Simon; Kabha, Eihab et al. (2014) Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G. Proc Natl Acad Sci U S A 111:E3187-95
Yefidoff-Freedman, Revital; Chen, Ting; Sahoo, Rupam et al. (2014) 3-substituted indazoles as configurationally locked 4EGI-1 mimetics and inhibitors of the eIF4E/eIF4G interaction. Chembiochem 15:595-611
Takrouri, Khuloud; Chen, Ting; Papadopoulos, Evangelos et al. (2014) Structure-activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein-protein interaction inhibitors. Eur J Med Chem 77:361-77