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.

项目总结： 急性髓系白血病(AML)是一种毁灭性的癌症，选择有限，尽管经过数十年的强化治疗 寻找治疗方法。AML的平均5年存活率约为30%(对所有患者而言)，但对于 大多数60岁以上的老年患者，2年生存率不到5%。约30%的急性髓细胞白血病患者 一种突变的Flt3激酶，这些患者的预后最差。米多妥林和吉曲替尼、Flt3抑制剂 分别于2017年和2018年获批。另一种Flt3抑制剂Crenolanib处于晚期临床III期 奎扎替尼在日本获得批准，但未能获得FDA的批准。然而，所有患者都在 四种Flt3抑制剂由于Flt3激酶的继发性突变而最终复发(如Flt3-ITD、D835 和F691突变体)和其他补偿抗性机制。乳腺癌的平均生存期为5年。 I期和II期的存活率为93%，但对一小部分但相当大的乳腺癌患者(15%-20%)来说， 那些患有激素难治性癌症(称为三阴性乳腺癌，TNBC)的人，治疗方法很少 选择。显然，需要对AML和TNBC癌症有效的新疗法。私人投资促进局 鉴定了仅在一个烧瓶中合成的新的基于~3H-吡唑并[4，3-f]喹啉的激酶抑制剂 操作，有效地抑制Flt3和/或CDK2或CDK12/13或CDK18。这些激动酶的选择性 取决于~3H-吡唑并[4，3-f]喹啉核的取代方式。CDK12/13和CDK18参与 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， 使此类癌症对损伤DNA或抑制DNA损伤修复的药物敏感，如阿霉素 或PARP抑制剂。该项目总体目标是优化这些有趣的新类别 用于可能转化为急性髓细胞白血病和乳房疗法的激酶抑制剂。在目标1中，第二代3H- 基于吡唑并[4，3-f]喹啉的化合物，(第一代化合物已经在体内显示出令人印象深刻的 体内治疗急性髓系白血病的疗效)，将在体内进行生化表征和评估(目标3)。额外的新功能 化学将被用来制造第三代~H-吡唑并[4，3-f]喹啉为基础的激酶抑制剂，这些药物具有 更好的类药物特性。目的2表征这些新的有效的抗增殖化合物如何影响蛋白质 肿瘤细胞的磷酸化，并测定化合物对各种AML细胞的杀伤能力 对目前的治疗方法如吉特利替尼耐药的乳腺癌细胞株和三阴性乳腺癌细胞株 体外培养。在AIMS 3中，PIs将评估铅化合物对AML和乳腺肿瘤的体内疗效。 抑制传统的Flt3(AML)和CDK12/13的AML和乳腺癌的新型药物 和CDK18，这是有趣的新癌症靶点，没有获得批准的靶向药物。