Pre-IND study of PMT-254, a pan-FLT3 inhibitor for the treatment of FLT3 driven cancers.

PMT-254 的 IND 前研究，PMT-254 是一种泛 FLT3 抑制剂，用于治疗 FLT3 驱动的癌症。

• 批准号: 8977931
• 负责人: Hong yu Li
• 金额: $ 28.58万
• 依托单位: PROMUTECH PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8977931
• 关键词: Acute Myelocytic Leukemia; BAY 54-9085; Biological Assay; Biopsy; California; Cancer Patient; Canis familiaris; Cell Line; Cells; Clinical; Data; Development; Dose; Drug Formulations; Drug Kinetics; Drug Packaging; Drug resistance; FLT3 gene; FLT3 inhibition; FLT3 inhibitor; Generations; Growth; Hour; Human; In Vitro; Inhibitory Concentration 50; Malignant Neoplasms; Medicine; Monitor; Mus; Mutation; Nature; Oral; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphotransferases; Plasma; Property; Rattus; Relapse; Research; Resistance; San Francisco; Series; Services; Sodium Chloride; Solubility; Therapeutic Agents; Time; Toxic effect; Toxicokinetics; Treatment outcome; Tumor Burden; Tumor Volume; Tyrosine Kinase Inhibitor; Universities; Western Blotting; Xenograft Model; Xenograft procedure; aqueous; drug development; effective therapy; in vivo; inhibitor/antagonist; kinase inhibitor; mutant; novel; organic acid; pre-clinical; public health relevance; therapeutic target; translational study; tumor

 DESCRIPTION (provided by applicant): Pathological activating mutations in the FLT3 kinase represent the most common genetic alteration in patients with acute myeloid leukemia (AML), occurring in approximately one third of cases. Recently, we performed translational studies that identified drug-resistant kinase domain mutations in FLT3-ITD at the time of relapse in AML patients treated with the FLT3 inhibitor, quizartinib (AC220), validating FLT3-ITD as a therapeutic target in human AML (N. Shah et al, Nature, 2012, 485, 260-263). To facilitate the rapid identification of potential therapeutic agents that can treat AML more effectively, a cancer with no newly approved efficacious treatments, we have created a novel fragment approach to discover kinase inhibitors and established a series of in vitro and in vivo assays to streamline the development of FLT3 inhibitors for AML. As a result, a highly potent FLT3 inhibitor clinical candidate, PMT-254, was identified. PMT-254 is the most potent, selective FLT3 inhibitor developed to date, displaying an IC50 of 0.009 nM for FLT-ITD transformed Ba/F3 cells. Further, PMT-254 achieves low nanomolar inhibition of quizartinib-resistant F691L, D835V, and D835Y mutants. Notably, all clinically-active investigational FLT3 inhibitors are much less potent and do not achieve a similar mutant activity profile. In human AML cell lines, PMT-254 achieves an IC50 of 0.15 nM in both MV4-11 and Molm-14 AML lines. In Molm-14 cells harboring an endogenous F691L or D835Y mutation, PMT-254 achieves a 0.226 nM or 2.2 nM IC50 value, respectively. PMT-254 does not impair the growth of parental Ba/F3 cells, even at a concentration of 10,000 nM. Screened against a kinase panel of 96 kinases, PMT-254 was found exclusively selective for FLT3 and FLT3 mutants. Clearly, PMT-254 is unlike any FLT3 inhibitor as manifested by its ultra-potency and ultra-selectivity, and therefore has extraordinary potential to transform treatment outcomes for patients with FLT3-ITD-driven AML. In MV4-11 xenograft studies, PMT-254 dosed PO 1.0 mg/kg shrunk tumors to undetectable levels in as little as four days (p <0.0001). Control tumors that reached a tumor volume of 1,200 mm3 were dosed at PO 1.0 and 0.3 mg/kg, which reduced tumor burden to undetectable levels in 11 days. Undetectable tumors from original treatment were allowed to rebound to a volume of 1,200 mm3 at which point treatment with PMT-254 commenced (PO 0.3 mg/kg), which again caused reduction in tumor volume to undetectable levels. Every mouse treated with PMT-254 was essentially cured of tumor burden and displayed no signs of toxicity even after receiving daily oral doses for over 40 consecutive days. In this proposal, we wish to further develop our FLT3 inhibitor by completing pilot formulation, PK/PD, and toxicity studies. This will acquire pivotal data necessary to justify completing an investigative new drug (IND) package. We have completed a preliminary 'proof of concept' data package, but specific facets to preclinical development are lacking that warrant additional pre-IND development. With the completion of this proposal, we will have a data package that will merit full IND development.

 描述（由适用提供）：FLT3激酶中的病理激活突变代表急性骨髓性白血病（AML）患者的最常见遗传改变，大约三分之一发生。最近，我们进行了翻译研究，在退休时在AML患者退休时鉴定了抗药性激酶结构域突变，接受了FLT3抑制剂，Quizartinib（AC220），将FLT3-ITD验证为Huml AML（N. Shah等人（N. Shah等人，2012年，2012年，485，260-260），将FLT3-ITD视为一种治疗靶标。为了促进可以更有效地治疗AML的潜在治疗剂的快速鉴定，没有新批准的有效治疗方法，我们创建了一种新型的片段方法来发现激酶抑制剂，并建立了一系列体外和体内测定法，以简化AML的FLT3抑制剂的开发。结果，确定了高潜在的FLT3抑制剂临床候选者PMT-254。 PMT-254是迄今为止开发的最潜力，选择性的FLT3抑制剂，用于FLT-ITD转化的BA/F3细胞的IC50为0.009 nm。此外，PMT-254可实现低纳摩尔抑制Quizartinib的F691L，D835V和D835Y突变体。值得注意的是，所有临床活跃的FLT3抑制剂的效力要少得多，并且没有达到类似的突变活性特征。在人AML细胞系中，PMT-254在MV4-11和MOLM-14 AML系中均达到0.15 nm的IC50。在具有内源性F691L或D835Y突变的Molm-14细胞中，PMT-254分别达到0.226 nm或2.2 nm IC50值。 PMT-254也不会损害父母BA/F3细胞的生长，即使浓度为10,000 nm。在96个激酶的激酶面板上筛选，发现PMT-254仅针对FLT3和FLT3突变体选择性。显然，PMT-254与任何FLT3抑制剂不同，因为其超功率和超级选择性表现出来，因此具有非凡的 改变FLT3-ITD驱动AML患者的治疗结果的潜力。在MV4-11的主体研究中，PMT-254 PO 1.0 mg/kg在短短四天内将肿瘤缩小到无法检测到的水平（P <0.0001）。以PO 1.0和0.3 mg/kg的形式将达到1,200 mm3的肿瘤体积的对照肿瘤进行了DOD，从而在11天内降低了肿瘤燃烧至无法检测到的水平。从原始治疗中未检测到的肿瘤可以反弹至1,200 mm3的体积，此时开始使用PMT-254（PO 0.3 mg/kg）进行处理，这再次导致肿瘤体积降低至无法检测到的水平。每种用PMT-254治疗的小鼠都可以用肿瘤燃烧治疗，并且即使连续40天接受每日口服剂量后，也没有表现出毒性的迹象。在此提案中，我们希望通过完成试点配方，PK/PD和毒性研究来进一步开发FLT3抑制剂。这将获得必要的关键数据，以证明完成调查新药（IND）软件包的合理性。我们已经完成了初步的“概念证明”数据包，但是缺乏临床前开发的特定方面，因此需要额外的预开发。随着该提案的完成，我们将拥有一个数据包，值得完整的IND开发。