Structure Based Design of Pol-theta inhibitors

Pol-theta 抑制剂的基于结构的设计

• 批准号: 10323627
• 负责人: Richard T Pomerantz
• 金额: $ 38.59万
• 依托单位: RECOMBINATION THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-16 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323627
• 关键词: Active Sites; Acute Myelocytic Leukemia; Acute leukemia; Adult; BRCA deficient; Binding Proteins; Biochemical; Biological Assay; Cells; Clinical; Collaborations; Combined Modality Therapy; Complex; Crystallization; DNA; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Repair Inhibition; DNA-Directed DNA Polymerase; Data; Diagnosis; Disease remission; Double Strand Break Repair; Drug Kinetics; Experimental Leukemia; FLT3 gene; Genetic; Genetic Recombination; Goals; In Vitro; Laboratories; Lead; Leukemic Cell; Liver Microsomes; Mediating; Methods; Mus; Mutation; Normal Cell; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Polymerase; Property; Proteins; RUNX3 gene; Resolution; Solubility; Stem cell transplant; Structure; Structure-Activity Relationship; Therapeutic; Tyrosine Kinase Inhibitor; X-Ray Crystallography; acute myeloid leukemia cell; base; brca gene; chemotherapy; deoxyribonucleoside triphosphate; design; drug candidate; drug development; high throughput screening; homologous recombination; in vivo; in vivo Model; inhibitor/antagonist; leukemia; nanomolar; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; patient subsets; personalized therapeutic; phase 1 study; phase 2 study; precision oncology; receptor; response; small molecule; standard of care; success; targeted treatment

Acute myeloid leukemia (AML) is the most frequently diagnosed form of acute leukemia in adults, and standard of care treatment involving chemotherapy and/or stem cell transplantation only cures 30-40% of patients. Recent studies show that AMLs with FLT3 receptor activating internal tandem duplication (ITD) mutations (FLT3(ITD)- positive AMLs) become defective in the BRCA1/2 pathway of homologous recombination (HR) following treatment with tyrosine kinase inhibitors (TKi). BRCA-deficiency confers strong sensitivity to DNA damage and/or DNA repair inhibition, and thus presents a promising new therapeutic strategy for AML. We discovered that BRCA-deficient leukemia cells are hyper-dependent on the DNA repair enzyme DNA polymerase theta (Polθ), which is dispensable for normal cells and mice. Polθ is involved in translesion synthesis and the microhomology-mediated end-joining (MMEJ) double-strand break (DSB) repair pathway. Our leading small- molecule Polθ inhibitor (Polθi) kills AML patient cells co-treated with the TKi quizartinib which causes BRCA-deficiency, whereas quizartinib and Polθi as single agents shows significantly less killing. These data demonstrate the Polθi + TKi combination as a promising therapeutic strategy for FLT3(ITD)-positive AML. Polθi also shows preferential killing of other BRCA-deficient leukemias (ALL, CML) in vitro and in vivo, especially in combination with TKi. In summary, our data discover Polθ as a novel drug target in leukemia, and demonstrate Polθi + TKi as a promising therapeutic strategy, especially in aggressive FLT3(ITD)-positive AML. In phase I, Recombination Therapeutics, LLC (RTx), a start-up precision oncology company, plans to increase the potency of our leading Polθi as a novel treatment for FLT3(IDT)-positive AML using X-ray crystallography and structure based optimization/design by developing the following Aims: 1. To solve the co-crystal structure of Polθ-DNA- Polθi ternary complexes; 2. To optimize Polθi using structure based optimization/design. In Phase II, RTx aims to achieve the following goals: 1. Further develop our leading Polθi drug candidate by achieving more favorable ADME and pharmacokinetic parameters; 2. Characterize optimized Polθi in combination with TKi in FLT3(IDT)-positive AML animal models in vivo.

急性髓性白血病（AML）是成人中最常诊断的急性白血病形式，并且标准的骨髓移植是治疗急性白血病的最佳方法。 涉及化疗和/或干细胞移植的护理治疗仅治愈30-40%的患者。最近 研究表明，具有FLT 3受体激活内部串联重复（ITD）突变（FLT 3（ITD）- 阳性AML）在BRCA 1/2同源重组（HR）途径中出现缺陷， 用酪氨酸激酶抑制剂（TKi）治疗。BRCA缺陷赋予对DNA损伤的强烈敏感性和/或 DNA修复抑制，从而提出了一个有前途的新的治疗策略AML。我们发现 BRCA缺陷型白血病细胞高度依赖DNA修复酶DNA聚合酶θ (Polθ），这对正常细胞和小鼠是不确定的。Polθ参与跨损伤合成， 微同源介导的末端连接（MMEJ）双链断裂（DSB）修复途径。我们领先的小- 分子Polθ抑制剂（Polθi）杀死与TKi quizartinib共同治疗的AML患者细胞， BRCA缺乏，而quizartinib和Polθi作为单一药物显示出显著更低的杀伤作用。这些 数据表明，Polθi + TKi联合治疗是FLT 3（ITD）阳性AML的一种有前景的治疗策略。 Polθi在体外和体内也显示出对其他BRCA缺陷型白血病（ALL，CML）的优先杀伤作用，尤其是 与TKi结合。总之，我们的数据发现Polθ是白血病的一个新的药物靶点， Polθi + TKi是一种有前景的治疗策略，尤其是在侵袭性FLT 3（ITD）阳性AML中。在第一阶段， 一家初创的精准肿瘤学公司，计划提高其效力， 我们领先的Polθi作为FLT 3（IDT）阳性AML的新型治疗方法，使用X射线晶体学和结构 基于优化/设计开发以下目标：1.为了解决Polθ-DNA-的共晶结构， Polθi三元配合物; 2.使用基于结构的优化/设计优化Polθi。 在第二阶段，RTx旨在实现以下目标：1.进一步开发我们领先的Polθi候选药物 通过实现更有利的ADME和药代动力学参数; 2.表征优化的Polθi， 在FLT 3（IDT）-阳性AML动物模型中，