Potent organometallic inhibitors of Signal Transducer and Activator of Transcript

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Current treatments for acute myeloid leukemia (AML) are inadequate to address the thousands of new cases diagnosed annually in the United States. Chemotherapy and bone marrow transplants are difficult and painful for patients, relapse rates approach 50%, and relapsed cancers are associated with poor prognosis. There is a large unmet need for new AML treatment options. The signal transducer and activator of transcription 3 (STAT3) protein is a potentially powerful new therapeutic target for the treatment of aggressive AML. Elevated levels of STAT3 activity speed tumor progression and increase lethality by inhibiting apoptosis, reducing immune responses, and facilitating drug resistance. STAT3 function is dependent on binding of its Src homology 2 (SH2) domain to a phosphotyrosine-containing peptide. The SH2 domain is a common protein fold that plays a role in numerous signaling pathways relevant to human disease, and developing potent drugs that target SH2 domains could have far-reaching impact. Unfortunately, while it is well understood that inhibiting STAT3 activity could have a dramatic and beneficial effect on tumor growth, developing drugs to target STAT3 is challenging. STAT3 and SH2-containing proteins in general, are examples of "undruggable" protein targets: they act through weak, transient interactions at shallow binding pockets and are resistant to inhibition with small molecules. Nonetheless, the link between STAT3 inhibitors and desirable effects on tumor growth has been conclusively demonstrated. Fundamentally new drug development approaches to effectively target STAT3 are needed to take advantage of this exciting new therapeutic opportunity. We plan to design, study, and develop hybrid organic-inorganic molecules as specific and potent inhibitors of STAT3. By combining molecular recognition with inorganic ligand coordination, we will design drug candidates with significantly improved potency and specificity in targeting STAT3. With initial funding from this grant, we will demonstrate potent binding of new inhibitor structures and their effect on STAT3 function in living cells. Assays for apoptosis activation and inhibition of AML colony formation will be conducted to evaluate therapeutic potential, and these studies will form a solid foundation for future animal and pre-clinical studies. This application wll establish organic-inorganic hybrids as a powerful and conceptually new class of potential drug molecules, with far-reaching applications and possibilities for applications in human health.