Most lung cancer cells are characterized by elevated levels of anti-apoptotic Bcl-2 family proteins and the resulting inhibition of cell-death influences tumorigenicity, metastatic behavior, chemoresistance and radioresistance. In non-small-cell lung cancer (NSCLC) upregulation of anti-apoptotic Bcl-2 proteins, such as Bcl-xL, Bcl-2 and Mcl-1, is often associated with resistance to traditional chemotherapy and radiation, which are therapeutic strategies that rely on the ability to induce apoptosis. Thus, novel optimized strategies for treatment of cancer might combine traditional chemotherapeutics with molecules that neutralize the effects of the anti-apoptotic Bcl-2 proteins. Already, Bcl-2- targeting antisense oligonucleotides (GenasenseTM) are in Phase III clinical trials for melanoma and chronic lymphocytic leukemia (CLL), a quintessential example of a human malignancy caused by defective programmed cell death and Bcl-xL/2 over- expression. Similarly, a dual Bcl-xL/Bcl-2 small molecule inhibitor (ABT-263, Abbott) is advancing clinical evaluation for patients affected by CLL. However, several studies suggest that in non-small cell lung cancers (NSCLC), in addition to Bcl-2 and Bcl-xL, Mcl-1 over-expression dictates resistance to chemotherapy and radiation. Hence, we propose to use a highly integrated multidisciplinary approach involving innovative structure-based design, medicinal chemistry, cell-based and in vivo studies to derive novel, potent and drug-like pan-Bcl-2 antagonists that primarily target Mcl-1, Bcl2 and Bcl-xL, focusing on their development against NSCLC. Given the arsenal of techniques and alternative approaches proposed, we anticipate that we will be able to identify novel pan-Bcl-2 antagonists that induce apoptosis in lung cancer cells that are resistant to current advanced compounds such as ABT-263 or Genasense.

Public Health Relevance

Alterations in the expression of the apoptosis-regulating Bcl-2 genes, including the protein Mcl-1, can contribute to the origins of non-small cell lung cancers (NSCLC), as well as adversely influence tumor responses to chemo- and radiotherapy. Therefore, agents that directly target Mcl-1 can induce apoptosis and sensitize cells to apoptosis induced by cytotoxic agents in lung cancer. The development of small molecule Mcl-1 inhibitors represent a promising route for the development of more effective combination therapies for the treatment of NSCLC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA149668-01
Application #
7866868
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Lees, Robert G
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2010-04-01
Budget End
2011-01-31
Support Year
1
Fiscal Year
2010
Total Cost
$396,325
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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
Wu, Bainan; Wang, Si; De, Surya K et al. (2015) Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells. Chem Biol 22:876-887
Barile, Elisa; De, Surya K; Feng, Yongmei et al. (2013) Synthesis and SAR studies of dual AKT/NF-?B inhibitors against melanoma. Chem Biol Drug Des 82:520-533
Goff, Daniel J; Court Recart, Angela; Sadarangani, Anil et al. (2013) A Pan-BCL2 inhibitor renders bone-marrow-resident human leukemia stem cells sensitive to tyrosine kinase inhibition. Cell Stem Cell 12:316-28
Thomas, Shibu; Quinn, Bridget A; Das, Swadesh K et al. (2013) Targeting the Bcl-2 family for cancer therapy. Expert Opin Ther Targets 17:61-75
Varadarajan, S; Bampton, E T W; Smalley, J L et al. (2012) A novel cellular stress response characterised by a rapid reorganisation of membranes of the endoplasmic reticulum. Cell Death Differ 19:1896-907
Jackson 2nd, Roger S; Placzek, William; Fernandez, Ana et al. (2012) Sabutoclax, a Mcl-1 antagonist, inhibits tumorigenesis in transgenic mouse and human xenograft models of prostate cancer. Neoplasia 14:656-65
Azab, Belal; Dash, Rupesh; Das, Swadesh K et al. (2012) Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) in combination with the Apogossypol derivative BI-97C1 (Sabutoclax) improves therapeutic efficacy in low CAR colorectal cancer cells. J Cell Physiol 227:2145-53
Hedvat, Michael; Emdad, Luni; Das, Swadesh K et al. (2012) Selected approaches for rational drug design and high throughput screening to identify anti-cancer molecules. Anticancer Agents Med Chem 12:1143-55
Rega, Michele F; Wu, Bainan; Wei, Jun et al. (2011) SAR by interligand nuclear overhauser effects (ILOEs) based discovery of acylsulfonamide compounds active against Bcl-x(L) and Mcl-1. J Med Chem 54:6000-13

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