instnjctions): Amplification of the gene encoding the anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) is a common genetic aberration in breast cancer. Mcl-1 overexpression in human cancers is associated with high tumor grade, resistance to chemotherapy and poor patient survival. Preclinical evidence suggests that Mcl-1 is a promising target for the treatment of breast cancers including the highly aggressive triple negative breast cancer (TNBC) subtype. Although attempts to target Mcl-1 have been reported, compounds specifically targeting Mcl-1 have not entered the clinic. Using a combination of fragment-based methods and structure- based design, we have discovered novel small molecules that bind to Mcl-1 with high affinity (KD - 35 nM) for the BH3-binding pocket, the motif used by Mcl-1 to bind to and sequester pro-apoptotic proteins. Therefore, we hypothesize that targeted inhibition of Mcl-1 will result in restoration of apoptotic signaling and increased sensitivity to chemotherapy in Mcl-1-dependent breast tumors. To test this hypothesis, we propose the following specific aims:
Aim 1. Discover potent (sub-nanomolar) and specific Mcl-1 inhibitors using fragment-based methods and structure-based design Aim 2. Optimize potent Mcl-1 inhibitors for their cell-based activities, pharmaceutical properties and In vivo efficacy in breast cancer models Aim 3. Identify genetic and molecular biomarkers of sensitivity to Mcl-1 inhibition, alone or in combination with other anticancer agents with a focus in TNBC

Public Health Relevance

Preclinical evidence suggests Mcl-1 is a common genetic alteration in breast cancer, including the virulent TNBC subtype. Development of rational and novel targeted drugs against this subtype of breast cancer is a major unmet need. We propose herein a translational project aimed at developing a potent and specific Mcl-1 inhibitor that will be ready for clinical trials within 5 years.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA098131-11
Application #
8593797
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Project Start
2003-08-07
Project End
2018-08-31
Budget Start
2013-09-17
Budget End
2014-08-31
Support Year
11
Fiscal Year
2013
Total Cost
$153,608
Indirect Cost
$67,607
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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