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: 10531587
• 负责人: Hong-Yu Li
• 金额: $ 63.97万
• 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/10531587
• 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; Data; Dependence; Development; Diagnosis; Disease; Disease Resistance; Docking; Dose Limiting; Drug resistance; Economic Burden; Evaluation; FLT3 gene; FLT3 inhibition; FLT3 inhibitor; Genes; Goals; Government; Grant; Hematology; Hematopoiesis; Human; In Vitro; Incidence; Lead; Life; Malignant Neoplasms; Mediating; Mediator; 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; Remission Induction; 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; 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.

项目摘要/摘要 酪氨酸激酶中的激活突变在人髓样恶性肿瘤中很常见。我们的长期目标是 通过基本和转化研究改善髓样恶性肿瘤患者的预后。 flt3是 急性髓样白血病（AML）中最常见的基因。这笔赠款的目的是建立 药物化学的最新进展正在推动目标治疗剂的界限，以进一步 告知激酶和疾病生物学，并覆盖靶向和脱离目标的发展机制 这些代理。中心假设是采用最先进的基础和转化研究 询问与临床上抗性疾病模型的分子工具将为您提供新的治疗方法 接近并促进我们对人类白血病生物学的理解。我们的理由是开创性的工作 在慢性髓样白血病中的BCR-ABL1上代表一个可以成功应用于其他的范式 髓样恶性肿瘤。以前，我们提供了令人信服的证据，以验证活化的FLT3作为治疗性 人类AML的目标。这项工作重新努力开发有效和选择性的FLT3激酶抑制剂， 最大程度地减少抗阻力支配次级激酶结构域突变的脆弱性，并导致 Gilteritinib的最新批准。但是，吉尔特替尼引起骨髓抑制，从而限制了其效用。我们的 临床前工作提名将RAS突变作为脱靶抗性的潜在介体，而我们的 吉尔替尼治疗的患者的最新翻译研究已证实活化的RA为主要 获得该药物的耐药机制。我们建议开发一流的FLT3酪氨酸激酶 抑制剂（TKI）不受靶向耐药性突变而没有血液毒性的抑制剂。我们 进一步提出的研究以识别和利用NRAS突变型FLT3-ITD阳性AML细胞中的脆弱性。我们的 具体目的将检验以下假设：（目标1）有效和选择性的FLT3抑制剂将具有 足够的治疗指数使它们能够保留对公共二次激酶结构域突变体的活性 并没有血液学毒性； （AIM 2）病理活化的FLT3和NRA的共存 将创建可以通过治疗剥削的新颖依赖性； （目标3）结构研究和 化合物优化可以鉴定具有类似药物的特性的活性化合物。结束这些 研究，我们将对化学支架有更详细的理解，这些脚手架有效，有选择地针对 FLT3，对包含共存的FLT3-ITD和NRAS突变的AML细胞的新了解，洞察 在这种情况下的治疗脆弱性和新颖的治疗学。这项贡献很重要，因为它具有 快速影响临床研究和治疗结果的潜力。拟议的研究是创新的 因为它建议将最先进的方法应用于系统探测分子 AML对靶向疗法具有抗药性的基础，并将其与化学方面的专业知识相结合 结构生物学。由于AML仍然与预后不良有关，因此这项工作可能具有很高的影响。