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（由申请人提供）：FLT3 激酶的病理激活突变是急性髓系白血病 (AML) 患者中最常见的遗传改变，发生在大约三分之一的病例中。最近，我们进行了鉴定耐药激酶的转化研究。使用 FLT3 抑制剂 quizartinib (AC220) 治疗的 AML 患者复发时 FLT3-ITD 的结构域突变，验证了 FLT3-ITD 作为治疗靶点人类 AML（N. Shah 等人，Nature，2012, 485, 260-263）为了促进快速鉴定能够更有效地治疗 AML（一种没有新批准的有效治疗方法的癌症）的潜在治疗药物，我们创建了一种新型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来简化用于 AML 的 FLT3 抑制剂的开发，因此，一种高效的 FLT3 抑制剂临床候选药物， PMT-254 被鉴定为迄今为止开发的最有效的选择性 FLT3 抑制剂，对 FLT-ITD 转化的 Ba/F3 细胞的 IC50 为 0.009 nM。此外，PMT-254 对 quizartinib 实现了低纳摩尔抑制。值得注意的是，所有具有临床活性的研究性 FLT3 抑制剂都具有耐药性 F691L、D835V 和 D835Y 突变体。在人 AML 细胞系中，PMT-254 在含有内源性 F691L 或 D835Y 的 Molm-14 细胞中的 IC50 为 0.15 nM。突变后，PMT-254 分别达到 0.226 nM 或 2.2 nM IC50 值。即使浓度为 10,000 nM，PMT-254 也不会损害亲代 Ba/F3 细胞的生长。针对 96 种激酶的激酶组进行筛选，发现 PMT-254 对 FLT3 和 FLT3 突变体具有特异性选择性。与任何 FLT3 抑制剂不同，其具有超强效力和超选择性，因此具有非凡的作用 在 MV4-11 异种移植研究中，口服 1.0 mg/kg 剂量的 PMT-254 在短短四天内将肿瘤缩小至不可检测的水平（p <0.0001）。肿瘤体积达到 1,200 mm3 的剂量为 PO 1.0 和 0.3 mg/kg，这将肿瘤负荷降低至不可检测的水平11 天内，原始治疗中无法检测到的肿瘤体积反弹至 1,200 mm3，此时开始使用 PMT-254（PO 0.3 mg/kg）进行治疗，这再次导致每只接受治疗的小鼠的肿瘤体积减小至无法检测到的水平。即使在连续 40 多天每天口服剂量后，使用 PMT-254 的肿瘤负荷也基本上被治愈，并且没有表现出毒性迹象。在本提案中，我们希望通过以下方式进一步开发我们的 FLT3 抑制剂。试点完成配方、PK/PD 和毒性研究。这将获得必要的关键数据，以证明完成新药研究 (IND) 包的合理性。我们已经完成了初步的“概念验证”数据包，但临床前开发的具体方面尚待确定。缺乏必要的额外预 IND 开发。随着该提案的完成，我们将拥有一个值得全面 IND 开发的数据包。