The design, synthesis, and characterization of potent and selective MEK7 inhibitors as targeted therapies for T-cell acute lymphoblastic leukemia

项目摘要 急性淋巴细胞性白血病(ALL)是儿童最常见的血液系统恶性肿瘤， 20岁之前最常见的癌症相关死亡原因。目前的治疗策略通过 非特定机制无法实现和维持近1/4的缓解 患有难治性疾病的儿科患者。虽然目前靶向治疗并不适用于所有人 患者，他们可以通过干预病理的细胞和分子来潜在地改善患者的预后 促进对多药化疗产生耐药性的活动。蛋白激酶MEK7的高表达 以及随后的MAP激酶下游信号的放大被确定为两个这样的过程 促进T细胞ALL(T-ALL)的化疗耐药，使MEK7成为T-ALL靶点 治疗。不幸的是，目前还没有已知的小分子能够有效和选择性地抑制这种MEK 异构体。利用我们发布的平台来询问整个MEK激酶家族的抑制剂选择性， 我们设计并合成了一种具有很强的MEK7抑制作用的先导化合物。我的目标是 本方案是对高效、选择性小分子MEK7的进一步开发和优化 抑制剂在T-ALL模型中化学探测MAPK通路这一臂中的异常信号。我们的 方法论需要一种多方面的方法，使用跨计算学科的策略 化学、有机合成、蛋白质生物化学和分子生物学。通过这些互补性 模式，我们试图获得对分子中最少被理解的MEK亚型的作用的新见解 T-ALL的病理生理学基础。最具临床意义的是，这项建议中的研究将调查 直接MEK7抑制剂作为T-ALL靶向治疗的疗效。

Project Summary Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in pediatric patients and the most frequent cause of cancer-related mortality before the age of 20. Current treatment strategies act by non-specific mechanisms that are incapable of achieving and maintaining remission in the nearly 1 out of 4 pediatric patients with therapy-resistant disease. While targeted therapies are not currently available for ALL patients, they could potentially improve patient outcomes by interfering with pathological cellular and molecular activities that facilitate resistance to multi-agent chemotherapy. Increased expression of protein kinase MEK7 and consequent amplification of downstream MAP kinase signaling have been identified as two such processes facilitating chemoresistance in T-cell ALL (T-ALL), rendering MEK7 an attractive target for T-ALL directed therapies. Unfortunately, there are no small molecules known to potently and selectively inhibit this MEK isoform. Leveraging our published platform for interrogating inhibitor selectivity across the MEK kinase family, we have designed and synthesized a lead compound exhibiting potent MEK7 inhibition. The objective of my present proposal is the further development and optimization of a potent and selective small molecule MEK7 inhibitor to chemically probe aberrant signaling in this arm of the MAPK pathway in T-ALL models. Our methodology entails a multifaceted approach employing strategies from disciplines spanning computational chemistry, organic synthesis, protein biochemistry, and molecular biology. Through these complementary modalities, we seek to gain new insight into the roles of the least understood MEK isoform in the molecular pathophysiology underlying T-ALL. Of utmost clinical significance, the studies in this proposal will survey the efficacy of direct MEK7 inhibitors as targeted therapies for T-ALL.