Structure Based Design of Pol-theta inhibitors

Pol-theta 抑制剂的基于结构的设计

基本信息

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
项目类别：
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

项目摘要

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.

急性髓系白血病 (AML) 是成人中最常诊断的急性白血病形式，标准涉及化疗和/或干细胞移植的护理治疗只能治愈 30-40% 的患者。研究表明，具有 FLT3 受体的 AML 激活内部串联重复 (ITD) 突变 (FLT3(ITD)- 阳性 AML）在同源重组 (HR) 的 BRCA1/2 途径中出现缺陷酪氨酸激酶抑制剂（TKi）治疗导致对 DNA 损伤和/或 BRCA 缺陷的强烈敏感性。 DNA 修复抑制，从而为 AML 提供了一种有前景的新治疗策略。 BRCA 缺陷的白血病细胞高度依赖 DNA 修复酶 DNA 聚合酶 theta (Polθ)，对于正常细胞和小鼠来说是可有可无的，其参与跨损伤合成和损伤。微同源介导的末端连接（MMEJ）双链断裂（DSB）修复途径。分子 Polθ 抑制剂 (Polθi) 可杀死与 TKi quizartinib 联合治疗的 AML 患者细胞，从而导致 BRCA 缺陷，而 quizartinib 和 Polθi 作为单一药物的杀伤力显着减少。数据表明 Polθi + TKi 组合作为 FLT3(ITD) 阳性 AML 的一种有前景的治疗策略。 Polθi 还显示出在体外和体内优先杀死其他 BRCA 缺陷型白血病（ALL、CML），特别是总之，我们的数据发现 Polθ 是白血病的新药物靶点，并证明了这一点。 Polθi + TKi 作为一种有前景的治疗策略，特别是在 I 期侵袭性 FLT3(ITD) 阳性 AML 中。 Recombination Therapeutics, LLC (RTx) 是一家初创精准肿瘤学公司，计划增强其功效使用 X 射线晶体学和结构分析我们领先的 Polθi 作为 FLT3(IDT) 阳性 AML 的新型治疗方法基于以下目标的优化/设计： 1. 解决Polθ-DNA-的共晶结构 2. 使用基于结构的优化/设计来优化 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 FLT3(IDT) 阳性 AML 动物模型中与 TKI 联合使用。