Development of Potent, Selective, Non-Myelotoxic FLT3 Inhibitors that Retain Efficacy Against Common Mechanisms of Resistance

开发有效的、选择性的、非骨髓毒性的 FLT3 抑制剂，保留对抗常见耐药机制的功效

• 批准号: 10314075
• 负责人: Hong-Yu Li
• 金额: $ 64.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10314075
• 关键词: ABL1 gene; Acute Myelocytic Leukemia; Address; Amino Acids; Apoptosis; Binding; Biological Assay; Biology; Cell Line; Cells; Chemicals; Chronic Myeloid Leukemia; Clinical; Clinical Trials; Computing Methodologies; Cost Measures; Crystallization; Data; Dependence; Development; Diagnosis; Disease; Disease Resistance; Disease remission; Docking; Dose-Limiting; Drug resistance; Economic Burden; Evaluation; FLT3 gene; FLT3 inhibitor; Genes; Goals; Government; Grant; Hematology; Hematopoiesis; Human; In Vitro; Incidence; Lead; Life; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical; Methodology; Minority; Modeling; Molecular; Molecular Probes; Mus; Mutagenesis; Mutate; Mutation; Myeloproliferative disease; Myelosuppression; Outcome; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphotransferases; Positioning Attribute; Prognosis; Property; Protein Kinase; Protein Tyrosine Kinase; Public Health; Recurrent disease; Research; Resistance; Resistance development; Roentgen Rays; Route; Sampling; Series; Specificity; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Agents; Therapeutic Index; Toxic effect; Tyrosine Kinase Inhibitor; Work; acute myeloid leukemia cell; base; clinical investigation; clinically relevant; cytotoxicity; design; disorder control; drug development; improved; improved outcome; in vivo; in vivo Model; inhibitor; inhibitor therapy; innovation; insight; kinase inhibitor; leukemia; mouse model; mutant; novel; novel therapeutic intervention; novel therapeutics; off-target mutation; pre-clinical; prevent; protein structure; resistance mechanism; resistance mutation; scaffold; structural biology; targeted treatment; therapeutic target; therapy outcome; tool; translational study

PROJECT SUMMARY/ABSTRACT Activating mutations in tyrosine kinase are common in human myeloid malignancies. Our long-term goal is to improve outcomes in patients with myeloid malignancies through basic and translational studies. FLT3 is the most commonly mutated gene in acute myeloid leukemia (AML). The objective of this grant is to build upon recent advances in medicinal chemistry that are pushing the boundaries of targeted therapeutics, to further inform kinase and disease biology, and to override evolving mechanisms of on- and off-target resistance to these agents. The central hypothesis is that basic and translational studies employing state-of-the-art molecular tools to interrogate clinically-relevant models of resistant disease will inform novel therapeutic approaches and advance our understanding of human leukemia biology. Our rationale is that pioneering work on BCR-ABL1 in chronic myeloid leukemia represents a paradigm that can successfully be applied to other myeloid malignancies. Previously, we provided compelling evidence validating activated FLT3 as a therapeutic target in human AML. This work rekindled efforts to develop potent and selective FLT3 kinase inhibitors that minimize vulnerabilities to resistance-conferring secondary kinase domain mutations in FLT3-ITD and led to the recent approval of gilteritinib. However, gilteritinib causes myelosuppression that limits its utility. Our preclinical work nominated activating RAS mutations as potential mediators of off-target resistance, and our recent translational studies of patients treated with gilteritinib have confirmed activated RAS as the dominant mechanism of acquired resistance to this drug. We propose to develop best-in-class FLT3 tyrosine kinase inhibitors (TKIs) that are impervious to on-target resistance mutations and devoid of hematologic toxicity. We further propose studies to identify and exploit vulnerabilities in NRAS-mutant FLT3-ITD-positive AML cells. Our specific aims will test the following hypotheses: (Aim 1) That potent and selective FLT3 inhibitors will have a sufficient therapeutic index to enable them to retain activity against common secondary kinase domain mutants and will be devoid of hematologic toxicity; (Aim 2) That coexistence of pathologically activated FLT3 and NRAS will create novel dependencies that can be exploited therapeutically; and (Aim 3) That structural studies and compound optimization can identify active compounds with drug-like properties. Upon conclusion of these studies, we will have a more detailed understanding of chemical scaffolds that potently and selectively target FLT3, novel understanding of AML cells that contain co-existent FLT3-ITD and NRAS mutations, insights into therapeutic vulnerabilities in this setting, and novel therapeutics. This contribution is significant since it has the potential to rapidly impact clinical investigation and therapeutic outcomes. The proposed research is innovative because it proposes application of state-of-the-art methodologies to systematically probe the molecular underpinnings of AML resistant to targeted therapeutics, and combine them with expertise in chemical structural biology. This work is potentially highly impactful as AML remains associated with a poor prognosis.

项目概要/摘要 酪氨酸激酶的激活突变在人类骨髓恶性肿瘤中很常见。我们的长期目标是 通过基础和转化研究改善骨髓恶性肿瘤患者的预后。 FLT3 是 急性髓系白血病 (AML) 中最常见的突变基因。这笔赠款的目的是建立在 药物化学的最新进展正在突破靶向治疗的界限，进一步 为激酶和疾病生物学提供信息，并克服靶向和脱靶耐药性的进化机制 这些代理。中心假设是基础研究和转化研究采用最先进的技术 研究耐药性疾病临床相关模型的分子工具将为新的治疗方法提供信息 方法并增进我们对人类白血病生物学的理解。我们的理由是开创性工作 慢性粒细胞白血病中 BCR-ABL1 的研究代表了一个可以成功应用于其他疾病的范例 骨髓恶性肿瘤。此前，我们提供了令人信服的证据来验证激活的 FLT3 作为一种治疗方法 人类 AML 的靶标。这项工作重新点燃了开发有效和选择性 FLT3 激酶抑制剂的努力 最大限度地减少 FLT3-ITD 中赋予抗性的二级激酶结构域突变的脆弱性，并导致 最近批准了gilteritinib。然而，吉特替尼会引起骨髓抑制，从而限制了其用途。我们的 临床前工作提名激活 RAS 突变作为脱靶耐药的潜在介质，我们的 最近对接受 gilteritinib 治疗的患者进行的转化研究证实，激活的 RAS 是主要的 对该药获得性耐药的机制。我们建议开发一流的 FLT3 酪氨酸激酶 不受靶向耐药突变影响且无血液毒性的抑制剂（TKI）。我们 进一步提出研究来识别和利用 NRAS 突变 FLT3-ITD 阳性 AML 细胞的漏洞。我们的 具体目标将检验以下假设：（目标 1）有效且选择性的 FLT3 抑制剂将具有 足够的治疗指数使它们能够保留针对常见二级激酶结构域突变体的活性 并且不会产生血液毒性； （目标 2）病理激活的 FLT3 和 NRAS 共存 将产生可用于治疗的新依赖性； （目标 3）结构研究和 化合物优化可以识别具有类似药物特性的活性化合物。完成这些后 研究，我们将对有效和选择性靶向的化学支架有更详细的了解 FLT3，对包含共存 FLT3-ITD 和 NRAS 突变的 AML 细胞的新认识，深入了解 这种情况下的治疗脆弱性和新颖的疗法。这一贡献意义重大，因为它具有 可能迅速影响临床研究和治疗结果。所提出的研究具有创新性 因为它提出应用最先进的方法来系统地探索分子 AML 对靶向治疗耐药的基础，并将其与化学专业知识相结合 结构生物学。这项工作具有潜在的巨大影响力，因为 AML 仍然与不良预后相关。