New ultra-selective kinase inhibitors for the treatment of AML

描述（由申请人提供）：急性髓性白血病（AML）在所有成人白血病病例中占很高的比例。虽然大多数患者一开始对常规化疗反应良好，但复发率高，患者对一线治疗难以耐受，预后非常差，5年生存率仅为14%。这一应用建立在我们发现新的高选择性激酶抑制剂的基础上，我们希望将其开发为治疗急性髓性白血病和其他癌症的新型靶向抗癌化合物。激酶抑制剂代表了一类新的抗癌药物，它们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的影响最小，因为它们专门针对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%的患者中发生突变并组成性激活。抑制这种突变的FLT-3激酶现在有望对这些患者有效，甚至作为单一疗法。我们已经鉴定出一种新的化合物GT-79，它与FLT-3野生型和突变型具有高亲和力。当在KinomeSCAN检测中对386种非突变激酶进行测试时，GT-79显示出特殊的激酶选择性，这与通过NCI-60筛选测试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具有出色的生物利用度，这表明GT-79是治疗AML的杰出新药候选药物。在这个应用中，我们建议1)进一步表征GT-79的激酶结合谱，探索GT-79及其类似物对FLT-3突变细胞系的生长抑制活性，并在体外和基于细胞的实验中研究FLT-3激酶的抑制作用

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.