Developing Novel STAT5 Protein Inhibitors for treatment of leukemias

描述(申请人提供)：信号转导和转录激活因子5(STAT5)是一种可诱导的转录因子，在许多癌症的进展中发挥关键作用，包括急性和慢性髓系白血病(AML，CML)。由人类白血病相关基因改变激活的激酶癌蛋白发出信号激活STAT5，遗传学实验表明，STAT5是这些癌蛋白在成人白血病的主要部分中必不可少的下游效应因子。虽然基因数据令人信服，但基因缺失并不是人类的功能性治疗方法。要证明STAT5是治疗白血病的靶点，需要在体内使用化学的STAT5抑制剂。针对上游STAT5激活酶的药物最初取得了成功，但存在获得性耐药、与较低的激酶选择性相关的靶外毒性以及激活STAT5的替代致癌途径等问题。此外，它们不直接抑制STAT5。这一提议的一个核心概念是，与STAT5-SH2结构域结合的小分子抑制了STAT5的激活，导致对STAT5活性的阻断。我们假设，使用集成的药物化学和白血病建模方法询问我们的STAT5-SH2结构域抑制物平台将获得第一个针对STAT5的小分子抑制物，用于体内解剖癌症生物学。我们期望验证STAT5作为治疗白血病的真正靶点，并提供简明的STAT5调节的生物标记物来评估人类AML中STAT5抑制剂的疗效。

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.