Hypoxia-Selective Kinase Inhibitors for Leukemia Therapy

用于白血病治疗的缺氧选择性激酶抑制剂

• 批准号: 8527296
• 负责人: Marina Y Konopleva
• 金额: $ 15.73万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-03 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527296
• 关键词: Accounting; Acute Myelocytic Leukemia; Amines; Ammonium; Antineoplastic Agents; Binding; Blast Cell; Bone Marrow; Cell Proliferation; Cells; Charge; Chemotherapy-Oncologic Procedure; Clinical; Clinical Data; Clinical Trials; Data; Development; Diagnosis; Disease-Free Survival; Dose; Drug Kinetics; Drug usage; Electrons; Environment; Foundations; Gene Mutation; Genes; Genetic; Goals; Human; Hypoxia; In Vitro; In complete remission; Lead; Lesion; Leukemic Cell; Life; Luciferases; Malignant Neoplasms; Modality; Modeling; Molecular; Mus; Mutate; Mutation; Normal Cell; Normal tissue morphology; Oncogenic; Pathologic; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphotransferases; Plasma; Prodrugs; Property; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Relapse; Reporting; Research Project Grants; Residual Neoplasm; Resistance; Role; Schedule; Side; Signaling Molecule; Sodium Chloride; Structure; Supporting Cell; Technology; Testing; Therapeutic; Therapeutic Index; Time; Toxic effect; Transplantation; Treatment Failure; Tyrosine Kinase Inhibitor; Universities; Vascular Endothelial Growth Factor Receptor-1; Xenograft Model; analog; anticancer research; base; bioluminescence imaging; cell growth; chemotherapy; combat; cytotoxic; cytotoxicity; design; disease characteristic; driving force; efficacy testing; improved; in vivo; inhibitor/antagonist; innovation; insight; kinase inhibitor; leukemia; metabolic abnormality assessment; mutant; novel; outcome forecast; pre-clinical; prevent; programs; prototype; public health relevance; receptor; research clinical testing; response; scaffold; scale up; small molecule; success; therapeutic target; tumor

DESCRIPTION (provided by applicant): Deregulation of cell proliferation in cancer and leukemia generally occurs following mutation and/or amplification of signalling molecules termed tyrosine kinases (TK). FLT3, a tyrosine kinase receptor, is the most commonly mutated gene in acute myeloid leukemia (AML) with internal tandem duplications (FLT3-ITD) occurring in 20-25% of patients. FLT3-ITD mutations are associated with aggressive disease characteristics, and FLT3 kinase inhibition can improve the otherwise poor prognosis of these leukemia patients. Although more than 20 small molecule inhibitors with inhibitory activity against FLT3 have been reported to date, clinical success of FLT3 inhibitors is largely limited by pharmacokinetic and pharmacodynamic difficulties in achieving sustained FLT3 inhibition without significant off-target toxicity. This indicates the need to broaden the therapeutic window of the FLT3 TKIs. In this proposal, we will utilize novel hypoxia-activated 'prodrug' technologies pioneered by Drs. Jeff Smaill and Adam Patterson at the University of Auckland. It takes advantage of the pathological hypoxia which was recently discovered by us as a prevalent environment of the leukemic but not normal bone marrow. The central hypothesis is that hypoxia-induced activation of TKIs in the leukemic BM niche would result in higher local concentrations of the drug with increased efficacy against leukemic blasts, while limiting toxicity to normal cells. In Aim 1, a hypoxia-activated prodrug strategy will be utilized to introduce increased tumour-selectivity to FLT3 inhibitors and thereby broaden their therapeutic index. As a prototype of this technology, hypoxia-activated irreversible pan-HER inhibitor PR610 was developed, and is scheduled to begin Phase I clinical testing in mid-2012. We will synthesise nitromethylaryl quaternary ammonium salt (NMQ) prodrugs of the known FLT3 inhibitors AC220, MLN-518, sunitinib and crenolanib. This class of prodrugs carry a permanent positive charge and are therefore excluded from cells, preventing binding of the kinase inhibitor with its intracellular kinase target in normal cells. In turn, the prodrug can undergo one-electron reduction and will fragment selectively under hypoxic conditions to release the cell permeable kinase inhibitor. This restricts normal tissue exposures and permits significantly greater doses to be administered (typically 50-100 fold increase in plasma AUC). We anticipate that the FLT3 pro-drugs would be the first prototype of hypoxia-activated TKI in leukemia. We will characterize the activity, selectivity and potency of FLT3 scaffolds in FLT3 mutated AML. MTD/PK/PD testing and in vivo efficacy studies in the FLT3-mutated xenograft model of human AML will be carried out in Aim 2. If successful, this approach will provide mechanism-based rationale for eliminating leukemic cells within the hypoxic BM niches and improve cure rates in AML.

描述（由申请人提供）：在癌症和白血病中细胞增殖的放松调节通常发生在突变和/或被称为酪氨酸激酶（TK）的信号分子的扩增后发生。 FLT3是一种酪氨酸激酶受体，是急性髓样白血病（AML）中最常见的突变基因，内部串联重复（FLT3-ITD）发生在20-25％的患者中。 FLT3-ITD突变与侵袭性疾病特征有关，而FLT3激酶抑制作用可以改善这些白血病患者原本不良的预后。 尽管据报道，迄今为止，已经有20多个具有抑制性FLT3活性的小分子抑制剂，但FLT3抑制剂的临床成功在很大程度上受到药代动力学和药效学难度在实现持续的FLT3抑制作用而没有明显的非目标毒性的情况下的限制。 这表明需要扩大治疗窗口 flt3 tkis。 在此提案中，我们将利用新型缺氧激活的“前药”技术 由博士开创。奥克兰大学的Jeff Smaill和Adam Patterson。 它利用了我们最近发现的病理缺氧，这是白血病的普遍环境，但不是正常的骨髓。 中心假设是缺氧引起的TKI在白血病BM生态位中的激活将导致该药物的局部浓度较高，而对白血病爆炸的疗效提高，同时限制了毒性 到正常细胞。 在AIM 1中，将利用缺氧激活的前药策略引入对FLT3抑制剂的肿瘤 - 选择性提高，从而扩大其治疗指数。 作为这项技术的原型，开发了缺氧激活的不可逆的泛抑制剂PR610，并计划于2012年中开始I期临床测试。 我们将合成已知的FLT3抑制剂AC220，MLN-518，Sunitinib和Crenolanib的硝基甲基四元铵盐（NMQ）前药。 这类前药具有永久性的正电荷，因此被排除在细胞中，以防止激酶抑制剂与正常细胞中其细胞内激酶靶靶标结合。 反过来，前药可以减少一单电子的还原，并在低氧条件下选择性碎片以释放细胞可渗透的激酶抑制剂。 这限制了正常的组织暴露，并允许施用更大的剂量（血浆AUC的增加50-100倍）。 我们预计FLT3亲毒品将是白血病中缺氧激活TKI的第一个原型。 我们将表征FLT3突变AML中FLT3支架的活性，选择性和效力。 MTD/PK/PD测试和人为AML的FLT3突变异种移植模型中的MTD/PK/PD测试和体内功效研究将在AIM 2中进行。如果成功，此方法将提供基于机制的基本原理，以消除低氧BM酸盐中的白血病细胞，并提高AML中的固化速率。