Given the pivotal role of anti-apoptotic Bcl-2 family proteins in cancer cell survival, development of anti-cancer therapeutics targeting the BH3 binding groove of anti-apoptotic Bcl-2 proteins has emerged as a promising, but difficult goal. Initial compounds targeted to the structure of Bcl-xL, and thereby able to bind to Bcl-2, Bcl-xL and Bcl-W, have shown promise in the clinic for the treatment of cancer, though studies have discovered that Mcl-1 over-expression allows cancers to evade treatment. To this end, the recent success with stable and cell permeable stapled BH3 peptides targeting Bcl-2 has provided the impetus to identify peptide sequences capable of selectively binding to Mcl-1 which is one major Aim of this proposal. If successful, our studies could result in advanced clinical candidates for the treatment of cancer. To test our hypotheses we will characterize and further determine the structural basis for inhibition, and subsequently we will test the potential anti-cancer activity of the proposed compounds in advanced pharmacological studies in cell and mice models of prostate cancer.

Public Health Relevance

Our studies are aimed at the identification of natural peptide sequences that target selectively an anti-apoptotic protein, Mcl-1, responsible for the onset of progression of most solid tumors. We will first characterize at the molecular level the structural basis for inhibition of Mcl-1, and subsequently we will test the potential anti- cancer activity of the proposed compounds in advanced pharmacological studies in cell and mice models of prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168517-03
Application #
8659353
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Arya, Suresh
Project Start
2012-07-09
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Bottini, Angel; Wu, Bainan; Barile, Elisa et al. (2016) High-Throughput Screening (HTS) by NMR Guided Identification of Novel Agents Targeting the Protein Docking Domain of YopH. ChemMedChem 11:919-27
Nakanishi, Yuki; Reina-Campos, Miguel; Nakanishi, Naoko et al. (2016) Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKCλ/ι. Cell Rep 16:3297-310
Menezes, M E; Das, S K; Minn, I et al. (2016) Detecting Tumor Metastases: The Road to Therapy Starts Here. Adv Cancer Res 132:1-44
Quinn, Bridget A; Lee, Nathaniel A; Kegelman, Timothy P et al. (2015) The Quest for an Effective Treatment for an Intractable Cancer: Established and Novel Therapies for Pancreatic Adenocarcinoma. Adv Cancer Res 127:283-306
Pan, Rongqing; Ruvolo, Vivian R; Wei, Jun et al. (2015) Inhibition of Mcl-1 with the pan-Bcl-2 family inhibitor (-)BI97D6 overcomes ABT-737 resistance in acute myeloid leukemia. Blood 126:363-72
Menezes, Mitchell E; Shen, Xue-Ning; Das, Swadesh K et al. (2015) MDA-7/IL-24 functions as a tumor suppressor gene in vivo in transgenic mouse models of breast cancer. Oncotarget 6:36928-42
Sarkar, Siddik; Quinn, Bridget A; Shen, Xue-Ning et al. (2015) Therapy of prostate cancer using a novel cancer terminator virus and a small molecule BH-3 mimetic. Oncotarget 6:10712-27
Wu, Bainan; Barile, Elisa; De, Surya K et al. (2015) High-Throughput Screening by Nuclear Magnetic Resonance (HTS by NMR) for the Identification of PPIs Antagonists. Curr Top Med Chem 15:2032-42
Kegelman, Timothy P; Das, Swadesh K; Emdad, Luni et al. (2015) Targeting tumor invasion: the roles of MDA-9/Syntenin. Expert Opin Ther Targets 19:97-112
Maji, Santanu; Samal, Sabindra K; Pattanaik, Laxmipriya et al. (2015) Mcl-1 is an important therapeutic target for oral squamous cell carcinomas. Oncotarget 6:16623-37

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