Discovery and Development of a Selective pan-FLT3-ITD Kinase Inhibitor Clinical Candidate for the Treatment of FLT3-ITD-Driven AML

 描述（由申请人提供）：急性髓性白血病（AML）是一种血液恶性肿瘤，其特征为异常白色血细胞的快速生长，干扰正常血细胞的产生。AML是一种毁灭性的恶性肿瘤，没有批准的靶向治疗，虽然罕见，但随着人口老龄化，发病率预计会急剧增加。在35%的病例中，FLT 3受体酪氨酸激酶发生功能获得性突变，使激酶具有组成性活性。大多数FLT 3激活突变作为内部串联重复（ITD）事件发生，产生无激酶结构域调节的癌基因。FLT 3-ITD癌基因能够转化血细胞的髓系，导致AML的发展和进展。为了治疗具有FLT 3-ITD致癌基因的AML，FLT 3抑制剂crenolanib和quizartinib正在进行临床研究。然而，这两种抑制剂的问题都源于毒性和瞬时功效的问题。使用quizartinib，大多数患者在开始治疗后4个月内复发，因为无法 抑制额外的FLT 3突变，crenolanib引起广泛的肝毒性。考虑到crenolanib和quizartinib的临床局限性，我们假设开发具有足够安全性特征的广谱FLT 3突变体抑制剂将在治疗FLT 3-ITD AML中非常有效。因此，我们建议启动一项药物发现活动，以开发一种抗突变的“泛FLT 3”抑制剂。同时，我们也希望评估两种具有不同突变体活性特征的FLT 3抑制剂的组合 以维持完全的FLT 3抑制，因为治疗选择产生了额外的突变。这需要开发两种独特的化合物，具有不同的FLT 3抑制机制。利用片段，X射线晶体结构和基于计算的药物发现方法，我们将开发FLT 3抑制剂，用于选择性突变FLT 3活性，并在生物化学，细胞和基于细胞的系统中评估安全性和有效性。随着这项研究的完成，我们预计将确定泛FLT 3临床候选药物和/或两种FLT 3抑制剂的联合治疗。如果成功，该项目将对FLT 3-ITD AML患者产生积极影响。

 DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is a hematological malignancy characterized by the rapid growth of abnormal white blood cells that interfere with the production of normal blood cells. AML is a devastating malignancy with no approved targeted therapy, and although rare, incidence is expected to increase dramatically as the population ages. In 35% of all cases, a gain-of-function mutation occurs in the FLT3 receptor tyrosine kinase that renders the kinase constitutively active. The majority of FLT3-activating mutations occur as internal tandem duplication (ITD) events, generating an oncogene with no kinase domain regulation. The FLT3-ITD oncogene is able to transform the myeloid line of blood cells, leading to the development and progression of AML. To treat AMLs with an FLT3-ITD oncogene, the FLT3 inhibitors crenolanib and quizartinib are under clinical investigation. However, problems with both inhibitors stem from issues of toxicity and transient efficacy. With quizartinib, most patients relapse within four months of starting treatment because of inability to inhibit additional FLT3 mutations, and crenolanib causes extensive liver toxicity. Taking into account the clinical limitations of both crenolanib and quizartinib, we hypothesize that the development of a broad spectrum FLT3 mutant inhibitor that possesses an adequate safety profile will be highly efficacious in treating FLT3-ITD AML. Therefore, we propose initiating a drug discovery campaign to develop a mutation-resistant "pan-FLT3" inhibitor. In parallel, we also wish to evaluate the combination of two FLT3 inhibitors with distinct mutant activity profiles in order to maintain complete FLT3 inhibition as additional mutations develop from treatment selection. This entails developing two unique compounds with mechanistically distinct FLT3 inhibitory profiles. Utilizing fragment, x-ray crystal structure, and computational-based drug discovery approaches, we will develop FLT3 inhibitor(s) for selective mutant FLT3 activity and evaluation in biochemical, cell, and mammalian-based systems for both safety and efficacy. With the completion of this study, we expect identification of a pan-FLT3 clinical candidate and/or a combination therapy of two FLT3 inhibitors. If successful, this project will positivity impact patients with FLT3-ITD AML.