Developing Novel STAT5 Protein Inhibitors for treatment of leukemias

描述（由申请人提供）：信号转导和转录激活因子5（STAT 5）是一种诱导型转录因子，在许多癌症的进展中起关键作用，包括急性和慢性髓性白血病（AML，CML）。由人类白血病相关遗传改变激活的激酶癌蛋白发出信号以激活STAT 5，并且遗传实验已经表明，STAT 5是成人白血病的主要部分中这些癌蛋白的必需下游效应物。虽然基因数据令人信服，但基因缺失并不是人类的功能性疗法。要证明STAT 5是治疗白血病的靶点，需要在体内使用化学STAT 5抑制剂。靶向上游STAT 5激活激酶的药物取得了初步成功，但受到获得性耐药性、与激酶选择性差相关的脱靶毒性和激活STAT 5的替代致癌途径的困扰。此外，它们不直接抑制STAT 5。该提议的核心概念是与STAT 5-SH 2结构域结合的小分子抑制STAT 5活化，导致对STAT 5活性的阻断。我们假设，使用整合的药物化学和白血病建模方法询问我们的STAT 5-SH 2结构域抑制剂平台将获得第一个STAT 5靶向小分子抑制剂，用于癌症生物学的体内解剖。我们期望验证STAT 5作为白血病治疗的真正靶点，并提供简洁的STAT 5调节的生物标志物来评估STAT 5抑制剂在人类AML背景下的疗效。

DESCRIPTION (provided by applicant): Signal Transducer and Activator of Transcription 5 (STAT5) is an inducible transcription factor that plays a pivotal role in the progression of many cancers, including acute and chronic myeloid leukemia (AML, CML). Kinase oncoproteins activated by human leukemia-relevant genetic alterations signal to activate STAT5, and genetic experiments have shown that STAT5 is a requisite downstream effector of these oncoproteins in a major fraction of adult leukemia. While the genetic data are compelling, genetic deletion is not a functional therapy in humans. Proving that STAT5 is a target for the treatment of leukemia requires the use of chemical STAT5 inhibitors in vivo. Drugs targeting upstream STAT5-activating kinases met with initial success, but are plagued with acquired resistance, off-target toxicity associated with poor kinase selectivity, and alternative oncogenic pathways activating STAT5. Moreover, they do not directly inhibit STAT5. A central concept underlying this proposal is that small molecule binding to the STAT5-SH2 domain inhibits STAT5 activation, resulting in a blockade to STAT5 activity. We hypothesize that interrogating our STAT5-SH2 domain inhibitor platform using an integrated medicinal chemistry and leukemia modeling approach will derive the first STAT5- targeted small molecule inhibitor for the in vivo dissection of cancer biology. We expect to validate STAT5 as a bona fide target for the treatment of leukemia, and to provide succinct STAT5-regulated biomarkers to evaluate STAT5-inhibitor efficacy in the context of human AML.