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.

急性髓样白血病（AML）是成人最常见的急性白血病形式，标准涉及化学疗法和/或干细胞移植的护理治疗只能治愈30-40％的患者。最近的研究表明，使用FLT3受体激活内部串联重复（ITD）突变的AML（FLT3（ITD） - 阳性AML）在同源重组（HR）之后的BRCA1/2途径中有缺陷用酪氨酸激酶抑制剂（TKI）治疗。 BRCA缺乏贡献对DNA损伤和/或 DNA修复抑制作用，因此为AML提供了有希望的新理论策略。我们发现了这一点缺乏BRCA的白血病细胞超过DNA修复酶DNA聚合酶theta （polθ），这对于正常细胞和小鼠来说是可分配的。 polθ参与了跨性别的合成和微学介导的最终连接（MMEJ）双链断裂（DSB）修复途径。我们领先的小型分子polθ抑制剂（POLθI）杀死与引起TKI Quizartinib共处的AML患者细胞 BRCA缺乏症，而作为单个药物的Quizartinib和Polθi的杀伤力明显较小。这些数据证明了POLθI + TKI组合是FLT3（ITD）阳性AML的有前途的治疗策略。 polθi还显示了在体外和体内的其他BRCA缺陷白血病（ALL，CML）的优先杀死，尤其是总而言之，我们的数据发现Polθ是白血病中的新药物目标，并证明了 Polθi + TKI是一种有希望的治疗策略，尤其是在侵略性FLT3（ITD）阳性AML中。在第一阶段，启动精度肿瘤公司Repompination Therapeutics，LLC（RTX）计划增加效力使用X射线晶体学和结构通过开发以下目的来基于优化/设计：1。解决POLθ-DNA-的共结晶结构 polθi三元络合物； 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。进一步发展我们的领先的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 在体内与TKI（IDT）阳性AML动物模型中的TKI结合。