BReast CAncer gene 1 (BRCA1) encodes for an 1863 amino acid protein. The C-terminus domains of BRCA1 (BRCT) interact with a variety of other proteins to facilitate cellular functions such as checkpoint regulation, DNA damage response and DNA repair. Mutations found in the BRCT domains of BRCA1, result in the formation of tumors in the breast and ovarian tissues. These mutations genetically predispose women to breast and ovarian cancers. However, retrospective clinical studies show that patients with mutations in the BRCT domains respond better to chemotherapy. M1775R is a cancer causing mutation found in the BRCT domains of BRCA1. The molecular basis for the cancer caused by the M1775R mutant protein has been attributed to the loss of BRCTM1775R binding to phosphorylated proteins, such as the carboxy helicase BACH1 (pBACH1). Biochemical and preclinical studies have shown that the BRCT-pBACH1 interaction is essential for check point regulation and DNA repair and cells carrying BRCT mutants are sensitive to DNA damaging chemotherapeutic agents. Taken together, these studies indicate that cancers with the BRCT mutations respond better to therapy due to the loss of BRCT DNA repair function. Using a combination of cell-free and cell-based assay we identified a small molecule inhibitor (BI-94) of the BRCT-pBACH1 interaction. We also show that BI-94 sensitizes breast cancer cells to growth inhibition and apoptosis induced by Etoposide and Bleomycin. In this application, we propose to continue these studies by 1) exploring if the resistance induced by the BRCT-pBACH1 interaction towards Bleomycin / Etoposide treatment extends to other breast and ovarian cancer therapeutics in specific aim 1 and 2) advance BI-94 / or a close analog as an anti-cancer agent through specific aims 2-4.PROJECT NARRATIVE In this application we propose to develop small molecule inhibitors of protein-protein interaction. The successful completion of this project will 1) provide valuable tools to understand the genesis and progression of cancers due to BRCA1 mutation and 2) provide lead compounds that can be developed as chemotherapeutic agents to treat sporadic breast and ovarian cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA127239-04
Application #
8117726
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Lees, Robert G
Project Start
2008-09-08
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$270,598
Indirect Cost
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Robb, Caroline M; Contreras, Jacob I; Kour, Smit et al. (2017) Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC). Chem Commun (Camb) 53:7577-7580
Gautam, Nagsen; Thakare, Rhishikesh; Rana, Sandeep et al. (2015) Irreversible binding of an anticancer compound (BI-94) to plasma proteins. Xenobiotica 45:858-73
Bailey, Tameka A; Luan, Haitao; Tom, Eric et al. (2014) A kinase inhibitor screen reveals protein kinase C-dependent endocytic recycling of ErbB2 in breast cancer cells. J Biol Chem 289:30443-58
Radhakrishnan, Prakash; Bryant, Vashti C; Blowers, Elizabeth C et al. (2013) Targeting the NF-ýýB and mTOR pathways with a quinoxaline urea analog that inhibits IKKýý for pancreas cancer therapy. Clin Cancer Res 19:2025-35
Rana, Sandeep; Natarajan, Amarnath (2013) Face selective reduction of the exocyclic double bond in isatin derived spirocyclic lactones. Org Biomol Chem 11:244-7
Chaturvedi, Nagendra K; Rajule, Rajkumar N; Shukla, Ashima et al. (2013) Novel treatment for mantle cell lymphoma including therapy-resistant tumor by NF-*B and mTOR dual-targeting approach. Mol Cancer Ther 12:2006-17
Gautam, Nagsen; Bathena, Sai Praneeth R; Chen, Qianyi et al. (2013) Pharmacokinetics, protein binding and metabolism of a quinoxaline urea analog as an NF-?B inhibitor in mice and rats by LC-MS/MS. Biomed Chromatogr 27:900-9
Nadeau, Scott; An, Wei; Palermo, Nick et al. (2012) Oncogenic Signaling by Leukemia-Associated Mutant Cbl Proteins. Biochem Anal Biochem Suppl 6:
Rajule, Rajkumar; Bryant, Vashti C; Lopez, Hernando et al. (2012) Perturbing pro-survival proteins using quinoxaline derivatives: a structure-activity relationship study. Bioorg Med Chem 20:2227-34
Pessetto, Ziyan Yuan; Yan, Ying; Bessho, Tadayoshi et al. (2012) Inhibition of BRCT(BRCA1)-phosphoprotein interaction enhances the cytotoxic effect of olaparib in breast cancer cells: a proof of concept study for synthetic lethal therapeutic option. Breast Cancer Res Treat 134:511-7

Showing the most recent 10 out of 21 publications