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

 描述(申请人提供)：急性髓系白血病(AML)是一种血液系统恶性肿瘤，其特征是异常白细胞迅速增长，干扰正常血细胞的产生。AML是一种破坏性的恶性肿瘤，没有得到批准的靶向治疗，虽然罕见，但随着人口老龄化，发病率预计会急剧增加。在所有病例中，35%的病例中，Flt3受体酪氨酸激酶发生了功能获得突变，使其具有结构性活性。大多数激活Flt3的突变发生在内部串联复制(ITD)事件中，产生的癌基因没有激酶域的调节。Flt3-ITD癌基因能够转化髓系血细胞，导致AML的发生发展。为了治疗带有Flt3-ITD癌基因的AML，flt3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疗效问题。使用奎扎替尼，大多数患者在开始治疗后四个月内复发，因为无法 抑制额外的Flt3突变，crenolanib会引起广泛的肝脏毒性。考虑到crenolanib和quizartinib的临床局限性，我们假设开发一种具有足够安全性的广谱Flt3突变抑制剂将在治疗Flt3-ITD AML方面非常有效。因此，我们建议发起一场药物发现活动，以开发一种耐突变的“PAN-Flt3”抑制剂。同时，我们还希望评估两种具有不同突变活性特征的Flt3抑制剂的组合。 以便在治疗选择产生更多突变时保持对Flt3的完全抑制。这需要开发两种独特的化合物，它们具有机械上不同的Flt3抑制谱。利用碎片、X射线晶体结构和基于计算的药物发现方法，我们将开发用于选择性突变Flt3活性的Flt3抑制剂(S)，并对其在生化、细胞和哺乳动物系统中的安全性和有效性进行评估。随着这项研究的完成，我们预计将确定PAN-Flt3临床候选药物和/或两种Flt3抑制剂的联合治疗。如果成功，该项目将对Flt3-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.