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Abstract
Grant Number: 1R21NS056915-01 Project Title: Discovery and characterization of novel small molecule inhibitors of Mcl-1
PI Information: Name Title NIKOLOVSKA-COLESKA, ZANETA zanetan@umich.edu Abstract: DESCRIPTION (provided by applicant): Myeloid cell leukemia-1 (Mcl-1) is a potent anti-apoptotic molecule and a member of the Bcl-2 family of proteins, which are central regulators of apoptosis. Although Mcl-1 is a homologous protein related to other anti-apoptotic proteins such as Bcl-2 and Bcl-xL, it has a distinctly different structure and specificity for its binding to other pro-death Bcl-2 members. Cancer cells that are highly resistant to small-molecule inhibitors of Bcl-2/Bcl-xL can become highly sensitive when Mcl-1 activity is eliminated by sRNAi, indicating the critical importance of Mcl-1 in maintaining cell survival. Mcl-1 has been to found to be overexpressed in both solid and non-solid tumor cell lines and human cancer tissues. Consistent with its anti-apoptotic function, overexpression of Mcl-1 has been associated with tumor initiation, progression and resistance to current anticancer therapies. Targeting Mcl-1 is therefore an important strategy for the development of new class of anticancer drugs for the treatment of cancer by overcoming apoptosis resistance. In this R21 grant, we propose to employ an experimental high throughout screening (HTS) approach for the discovery of novel, small-molecule inhibitors of Mcl-1. Identified hits will be evaluated in a series of complementary biochemical, biophysical, functional and cellular assays to rule out any potential false positives and to determine their specificity and mechanism of action. We will pursue the following specific Aims: (1) HTS using FP and HTRF based assay; (2) Conformation of the identified hits and their selectivity and specificity in binding by using different biochemical and biophysical assays (ELISA, FP and NMR); (3) Characterization of their: i) effect on cytochrome c release from isolated mitochondria; ii) ability to disrupt the dimerization of Mcl-1 with pro- apoptotic Bcl-2 members in live cells; iii) their activity and selectivity in cell-growth inhibition of cancer cells and normal cells; iv) potency in induction of apoptosis in cancer cells and model cells. Successfully carried out, our studies will provide a number of novel, small-molecule inhibitors of Mcl-1 with detailed characterization of their binding affinity to Mcl-1 and specificity over other proteins, their cellular activity and function. Such well-characterized small-molecule inhibitors of Mcl-1 will not only serve as promising lead compounds for further optimization toward developing a new class of anticancer drugs, but may also be used as a set of much needed pharmacological tools for further elucidation of the functions of Mcl-1.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
BCL2 gene /protein, drug discovery /isolation, inhibitor /antagonist, small molecule
apoptosis, biological signal transduction, conformation, cytochrome c, dimer, protein binding
NIH Roadmap Initiative tag, high throughput technology
Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR 3003 SOUTH STATE STREET, Room 1040 ANN ARBOR, MI 481091274 Fiscal Year: 2006 Department: INTERNAL MEDICINE Project Start: 05-JUL-2006 Project End: 30-JUN-2009 ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE IRG: ZNS1