This application proposes to develop a new type of strategy for selectively killing cancerous cells in cases of breast cancer and diffuse large B-cell lymphoma. Breast cancer is the second most common cause of cancer death in Texas women, and diffuse large B-cell lymphoma is the most common type of lymphoma. Growth of each of these types of cancers can be stimulated by a specific protein called BCL6. Earlier tests have shown that when the function of this protein is blocked, cancerous cells can be killed but the surrounding normal cells are spared. Accordingly, there have been efforts from academic and industrial labs to make molecules that block BLC6, but these efforts have had shortcom...

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This application proposes to develop a new type of strategy for selectively killing cancerous cells in cases of breast cancer and diffuse large B-cell lymphoma. Breast cancer is the second most common cause of cancer death in Texas women, and diffuse large B-cell lymphoma is the most common type of lymphoma. Growth of each of these types of cancers can be stimulated by a specific protein called BCL6. Earlier tests have shown that when the function of this protein is blocked, cancerous cells can be killed but the surrounding normal cells are spared. Accordingly, there have been efforts from academic and industrial labs to make molecules that block BLC6, but these efforts have had shortcomings that have prevented them from producing approved drugs. In our work, we plan to develop a new way to specifically and irreversibly block BCL6. Essentially, we design molecules that stay relatively inert during their administration, but become very reactive upon binding BCL6. After binding, these molecules make an irreversible bond to BCL6 that results in potent irreversible inhibition. We will design and make a panel of novel chemical compounds and optimize their drug-like properties by improving their selectivity, affinity, and efficacy. Our studies will first determine the interactions of these new chemical compounds with purified BCL6 protein and then extend the work into cell lines originally derived from patients with triple-negative breast cancer or diffuse large B-cell lymphoma. If successful, our strategy will enable us to effectively turn off BCL6 in cancerous cells. This study will have an impact by establishing a new strategy for making drug candidate molecules for difficult-to-target oncoproteins, and the chemical compounds we make will serve as precursors for future anticancer therapeutics.

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