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）是成人急性白血病最常见的诊断形式，也是标准的