3H-pyrazolo[4,3-f]quinoline-containing compounds as selective and tunable protein kinase inhibitors

含 3H-吡唑并[4,3-f]喹啉的化合物作为选择性和可调节的蛋白激酶抑制剂

• 批准号: 10364366
• 负责人: Reuben Kapur
• 金额: $ 49.58万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-10 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364366
• 关键词: ADME Study; Acute Myelocytic Leukemia; Affect; Antineoplastic Agents; Aromatase Inhibitors; Attention; Autopsy; BRCA mutations; Binding; Binding Proteins; Biochemical; Brain; Breast; Breast Cancer Patient; Breast Cancer cell line; CDC2 gene; CDK2 gene; CDK4 gene; Cancer Model; Cancer Patient; Caspase; Cell Cycle; Cell Cycle Progression; Cell Death; Cell Line; Cell physiology; Cells; Chemistry; Clinic; Clinical; Clinical Trials; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Cyclins; Cytochrome P450; DNA Damage; DNA Repair; Data; Development; Dose; Doxorubicin; Drug Kinetics; Drug Targeting; Drug resistance; Enzymes; Estrogen Receptors; Estrogen receptor positive; Evaluation; Excipients; FLT3 gene; FLT3 inhibitor; FRAP1 gene; Fulvestrant; Generations; Genetic Transcription; Goals; Heart; Hematologic Neoplasms; Histology; Hormones; Hydrolase; In Vitro; Indiana; Japan; Lead; Letrozole; Liver; Lung; MEKs; Malignant Neoplasms; Mammary Neoplasms; Maximum Tolerated Dose; Mediating; Mus; Mutate; Mutation; Oncogenic; Oncology; Oral; Organ; Outcome; PI3K/AKT; Pathologic; Pathway interactions; Patients; Pattern; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase I/II Clinical Trial; Phase III Clinical Trials; Phosphorylation; Phosphotransferases; Property; Relapse; Resistance; Secondary to; Serum; Serum Proteins; Signal Pathway; Solid Neoplasm; Solubility; Specialist; Spleen; Survival Rate; Therapeutic; Time; Toxic effect; Transcriptional Regulation; Translations; Tumor Biology; Xenograft Model; acute myeloid leukemia cell; base; biophysical properties; cancer cell; cancer therapy; clinical candidate; curative treatments; efficacy study; experience; flasks; in vivo; inhibitor; kinase inhibitor; leukemia; malignant breast neoplasm; medical schools; mutant; nanomolar; novel; novel therapeutics; older patient; operation; pre-clinical; protein kinase inhibitor; quinoline; refractory cancer; resistance mechanism; response; scaffold; scale up; triple-negative invasive breast carcinoma; tumor growth

Project summary: Acute myeloid leukemia (AML) is a devastating cancer with limited options, despite decades of intensive searches for curative therapeutics. The average 5-year survival of AML is about 30% (for all patients) but for most elderly patients over 60 years, the 2-year survival rate is less than 5%. About 30% of AML patients harbor a mutated FLT3 kinase and these patients have the worst outcome. Midostaurin and gilteritinib, FLT3 inhibitors were approved in 2017 and 2018 respectively. Crenolanib another FLT3 inhibitor is in advanced phase III clinical trials, whereas quizartinib was approved in Japan but failed to gain FDA approval. However patients on all of the four FLT3 inhibitors ultimately relapse due to secondary mutations in the FLT3 kinase (such as FLT3-ITD, D835 and F691 mutants) and other compensatory resistance mechanisms. Breast cancer has an average 5-year survival rate is 93% for stage I and II but for a small but significant percentage (15-20%) of breast cancer patients, who harbor hormone refractory cancer (called triple negative breast cancer, TNBC), there are few therapeutic options. Clearly new therapeutics, which are effective against AML and TNBC cancers, are needed. The PIs have identified novel 3H-pyrazolo[4,3-f]quinoline-based kinase inhibitors, synthesized in only a single flask operation, that potently inhibit FLT3 and/or CDK2 or CDK12/13 or CDK18. The selectivity for these kinases depend on the substitution pattern of the 3H-pyrazolo[4,3-f]quinoline core. CDK12/13 and CDK18 are involved in the cell's response to DNA damage and the inhibition of these kinases lead to BRCAness in various cancers, making such cancers sensitive to agents that damage DNA or inhibit DNA damage repair, such as doxorubicin or PARP inhibitors respectively. The overall goal of this project is to optimize these interesting new class of kinase inhibitors for possible translation into AML and breast therapeutics. In aim 1, second-generation 3H- pyrazolo[4,3-f]quinoline-based compounds, (first-generation compounds have already shown impressive in-vivo efficacy against AML in vivo), will be biochemically characterized and evaluated in vivo (Aim 3). Additionally new chemistries will be used to make third-generation 3H-pyrazolo[4,3-f]quinoline-based kinase inhibitors that have better drug-like properties. Aim 2 characterize how these new potent anti-proliferative compounds affect protein phosphorylation in cancer cells and to determine the potencies of the compounds at killing various AML cell lines, which are resistant to current therapies such as gilteritinib, and triple negative breast cancer cell lines in vitro. In aims 3, the PIs will evaluate the in-vivo efficacies of lead compounds against AML and breast tumors. project, novel agents against AML and breast cancer, which inhibit traditional FLT3 (AML) as well as CDK12/13 and CDK18, which are interesting new cancer targets with no approved drugs that target them.

项目摘要： 急性髓样白血病（AML）是一种毁灭性的癌症，尽管数十年 寻找治疗疗法。 AML的平均5年生存率约为30％（对于所有患者），但对于 大多数老年患者在60年内，2年的生存率小于5％。大约30％的AML患者港口 突变的FLT3激酶和这些患者的结果最差。 Midostaurin和Gilteritinib，FLT3抑制剂 分别在2017年和2018年获得批准。 crenolanib另一种FLT3抑制剂在晚期III期临床中 试验，而Quizartinib在日本获得批准，但未能获得FDA批准。但是所有患者 四个FLT3抑制剂最终由于FLT3激酶的次级突变而最终复发（例如FLT3-ITD，D835 和F691突变体）和其他补偿性抗性机制。乳腺癌平均有5年 I和II期的生存率为93％，但对于乳腺癌患者的少数但很大的百分比（15-20％）， 谁怀有激素难治性癌（称为三重阴性乳腺癌，TNBC），几乎没有治疗 选项。显然，需要对AML和TNBC癌症有效的新疗法。 pis 已经鉴定出新型的3H-吡唑[4,3-F]喹啉的激酶抑制剂，仅在单个烧瓶中合成 操作，可有效抑制FLT3和/或CDK2或CDK12/13或CDK18。这些激酶的选择性 取决于3H-pyrazolo [4,3-F]喹啉核心的替代模式。 CDK12/13和CDK18涉及 在细胞对DNA损伤的反应中，这些激酶的抑制导致了各种癌症的Brcaness， 使这样的癌症对损害DNA或抑制DNA损伤修复的药物敏感，例如阿霉素 或PARP抑制剂。该项目的总体目标是优化这些有趣的新类 激酶抑制剂可能转化为AML和乳房疗法。在AIM 1中，第二代3H- 吡唑洛[4,3-f]基于喹啉的化合物（第一代化合物已经显示出令人印象深刻的体体内化合物 对AML在体内的功效）将在体内对生化表征和评估（AIM 3）。另外是新的 化学物质将用于制造第三代3H-pyrazolo [4,3-F]喹啉基酶抑制剂 更好的类药物特性。 AIM 2表征了这些新的有效抗增殖化合物如何影响蛋白质 癌细胞中的磷酸化，并确定化合物杀死各种AML细胞的效力 线，对当前疗法（例如吉尔特替尼）的抗性和三重阴性乳腺癌细胞系 体外。在AIMS 3中，PIS将评估针对AML和乳腺肿瘤的铅化合物的体内效力。 项目，针对AML和乳腺癌的新型药物，抑制传统的FLT3（AML）以及CDK12/13 和CDK18，是有趣的新癌症靶标，没有批准的药物。