New ultra-selective kinase inhibitors for the treatment of AML

描述（由申请人提供）：急性髓系白血病（AML）占所有成人白血病病例的很高比例。虽然大多数患者最初对常规化疗反应良好，但复发率很高，患者对一线治疗难以耐受，一线治疗的疗效非常差，五年生存率仅为14%。该应用建立在我们发现新的高选择性激酶抑制剂的基础上，我们希望开发新的靶向抗癌化合物，用于治疗AML和其他癌症。激酶抑制剂代表了一类新的抗癌药物，其可以非常特异性地杀死癌细胞，同时对正常健康组织和器官具有最小的影响，因为它们特异性地靶向肿瘤细胞生长所必需的分子。这种“靶向药物”的开发是可能的，因为已经发现了导致某些癌症的特定缺陷。在AML中，酪氨酸激酶受体FLT-3在高达40%的患者中突变并组成性激活。抑制这种突变的FLT-3激酶现在有望成为有效的，甚至作为这些患者的单一疗法。我们已经鉴定了一种新型化合物GT-79，其以高亲和力结合FLT-3野生型和突变型。当在KinomeSCAN测定中针对386种非突变激酶进行测试时，GT-79显示出卓越的激酶选择性，这与通过在NCI-60筛选中进行测试而确定的最佳靶向抗癌活性相关。重要的是，我们最近的数据表明GT-79具有优异的生物利用度，这表明GT-79是治疗AML的杰出新药候选物。在本申请中，我们提出1）进一步表征GT-79的激酶结合谱，探索GT-79和类似物对FLT-3突变细胞系的生长抑制活性，并在体外和基于细胞的测定中研究FLT-3激酶的抑制 （具体目标1）;和2）使用两种AML异种移植模型：MV 4 -11和MOLM-13细胞研究GT-79的体内抗癌功效;这些动物实验还将允许对GT-79进行初步毒性评价（特定目标2）。确定GT-79的疗效和安全性，并进一步确定其激酶结合谱和FLT-3突变对其疗效的依赖性，将使我们处于最佳位置，以推动GT-79在后续II期应用中进入完整的临床前和早期临床研究。一旦我们证明了GT-79在AML异种移植物中的疗效，我们还将评估GT-79治疗实体瘤的效果，包括GIST、甲状腺髓样癌和可能的某些肾癌。 公共卫生相关性：拟定的研究与开发用于治疗AML和其他癌症的新型FLT-3抑制剂相关。激酶抑制剂已经证明对许多癌症有效，其中突变的激酶在癌细胞生长中起主要作用。这些所谓的靶向抗癌药物的成功例子是格列卫，易瑞沙，以及最近的几种其他分子。在近40%的AML患者中发现FLT-3突变，已将FLT-3确定为开发用于治疗AML的新型靶向疗法的有希望的靶点。不幸的是，大多数早期的FLT-3抑制剂不是非常有选择性或缺乏足够的生物利用度，并且由于sde效应和/或无效而在临床上失败。然而，这些早期化合物中的一些仍在作为辅助疗法进行评估。一个突出的例外是一个非常有选择性的高亲和力化合物（AC 220），现在已经显示出有希望的结果作为单一治疗的第二阶段疗效研究。这表明，高选择性激酶抑制剂在临床上可以取得成功，而选择性较低的化合物往往失败。我们已经确定了一种新的高选择性，高亲和力FLT-3抑制剂（GT-79），显示出良好的生物利用度在体内。我们建议开发GT-79，它代表了一种独特的化学实体，不同于其他FLT-3抑制剂，作为AML和随后其他癌症的新靶向治疗。

DESCRIPTION (provided by applicant): Acute Myeloid Leukemia (AML) accounts for a high percentage of all adult leukemia cases. Although most patients at first respond well to conventional chemotherapy, there is a high rate of relapse and patients become refractory to front-line treatment, which bears very poor prognoses and a five-year survival rate of only 14%. This application builds on our discovery of new highly selective kinase inhibitors that we want to develop as novel targeted anticancer compounds for the treatment of AML and later for other cancers as well. Kinase inhibitors represent a new class of anticancer drugs that can very specifically kill a cancer cell while having minimal effects on normal healthy tissues and organs because they target specifically molecules that are necessary for tumor cell growth. Development of such 'targeted drugs' is possible because of discoveries that have pinpointed the specific defects that cause certain cancers. In AML, the tyrosine kinase receptor FLT-3 is mutated and constitutively activated in up to 40% of patients. Inhibiting this mutant FLT-3 kinase now promises to be effective even as a mono therapy for these patients. We have identified a novel compound, GT-79 that binds with high affinity to FLT-3 wild type and mutant forms. GT-79 shows exceptional kinase selectivity when tested against 386 non-mutated kinases in a KinomeSCAN assay, which correlates with optimally targeted anticancer activity as established through testing in the NCI-60 screen. Importantly, our recent data demonstrate that GT-79 has excellent bioavailability, which suggests GT-79 as an outstanding new drug candidate for the treatment of AML. In this application we propose to 1) further characterize the kinase binding profile of GT-79, explore the growth inhibitory activity of GT-79 and analogs against FLT-3 mutant cell lines, and investigate the inhibition of FLT-3 kinase in vitro and in cell-based assays (Specific Aim 1); and to 2) investigate the anticancer efficacy of GT-79 in vivo using two AML xenograft models: MV4-11 and MOLM-13 cells; these animal experiments will also allow for a preliminary toxicity evaluation of GT-79 (Specific Aim 2). Establishing the efficacy and safety of GT-79 and further establishing its kinase binding profile and FLT-3 mutation dependence for its efficacy will place us in an optimal position to advance GT-79 into full preclinical and early clinical studies in a subsequent Phase II application. Once we have proven the efficacy of GT79 in AML xenografts, we will also evaluate GT-79 for the treatment of solid tumors, including GISTs, medullary thyroid cancer, and possibly certain renal cancers. PUBLIC HEALTH RELEVANCE: The proposed studies are relevant to the development of novel FLT-3 inhibitors for the treatment of AML and other cancers. Kinase inhibitors have demonstrated effectiveness against a number of cancers where mutated kinases play a major role in cancerous cell growth. Successful examples of these so-called targeted anticancer drugs are Gleevec, Iressa, and more recently several other molecules. The discovery of FLT-3 mutations in nearly 40% of AML patients has identified FLT-3 as a promising target to develop novel targeted therapies for the treatment of AML. Unfortunately, most early FLT-3 inhibitors were not very selective or lacked sufficient bioavailability and have failed in the clinic due to sde effects and/or inefficacy. However some of these early compounds are still being evaluated as adjuvant therapies. One outstanding exception is a very selective high affinity compound (AC220) that has now shown promising results as mono therapy in a Phase II efficacy study. This demonstrates that highly selective kinase inhibitors can be successful in the clinic where less selective compounds often fail. We have identified a novel highly selective, high affinity FLT-3 inhibitor (GT-79) that shows excellent bioavailability in vivo. We propose to develop GT-79, which represents a unique chemical entity distinct from other FLT-3 inhibitors, as a new targeted treatment for AML and subsequently other cancers.