Bcl-2 selective inhibitors: development and application to cancer treatment

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DESCRIPTION (provided by applicant): Drug resistance is a significant stumbling block in the fight against cancer. Small molecules that inhibit anti- apoptotic Bcl-2 proteins have the potential to overcome such drug resistance. Most of current small- molecule inhibitors non-selectively target multiple anti-apoptotic Bcl-2 proteins. It remains to be determined: 1) whether a selective inhibitor will be effective in overcoming drug resistance; 2) whether non-selectively inhibiting multiple anti-apoptotic Bcl-2 proteins may introduce more toxicity against healthy tissues; 3) whether non-selectively inhibiting multiple anti-apoptotic Bcl-2 proteins may be less effective in the treatment of certain cancers since it is questionable that all endogenous anti-apoptotic Bcl-2 proteins have protective functions in all tumors. Our long-term goal is to develop chemical probes for anti-apoptotic Bcl-2 proteins to help study their functions in various tumors and to develop small-molecule inhibitors for cancer treatment. Our central hypothesis for this proposed research is that member-selective inhibitors of anti-apoptotic Bcl-2 proteins will selectively induce / sensitize the cancers that overexpress such a protein to apoptosis. This central hypothesis is formulated based on the following observations. First, though some tumors simultaneously overexpress multiple anti-apoptotic Bcl-2 proteins, many tumors only overexpress a single anti-apoptotic Bcl- 2 protein. The selective overexpression of one anti-apoptotic Bcl-2 protein suggests that a selective inhibitor would be effective in overcoming the drug resistance. Second, a Bcl-2 inhibitor identified by Wang et al (YC 137) selectively induces apoptosis in a tumor cell line that overexpresses Bcl-2 protein and shows less toxicity to normal cells. Third, a Bcl-2 selective inhibitor identified in our laboratory can effectively overcome the drug resistance induced by Bcl-2 overexpression (Preliminary Studies). Based on these observations, the focus of this proposal is on the development of selective inhibitors for anti-apoptotic Bcl-2 proteins and their evaluation against primary tumors for cancer treatment. The specific aims are to: 1. Identify a set of inhibitors for Bcl-2, Bcl-XL, and Bcl-w with stringent selectivity (two for each protein). We will 1) rationally design and synthesize a 72-member library based on a promising template by using molecular modeling and solid-phase synthesis; 2) identify the selective inhibitors by a solid-phase assay; and 3) determine their absolute binding selectivity. 2. Examine the effect of binding selectivity on the potential for selective toxicity to tumors over healthy tissues and the potential of sensitizing tumors to conventional cancer treatment. We will 1) evaluate our current selective and non-selective inhibitors for their cytotoxicity against hematologic primary tumors and healthy blood cells; 2) evaluate our current selective inhibitors for their potential synergism with clinical therapies against the hematologic primary tumors.