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

基本信息

批准号：
10620305
负责人：
Reuben Kapur
金额：
$ 45.22万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10620305
关键词：
70-kDa Ribosomal Protein S6 Kinases ADME Study Acute Myelocytic Leukemia Affect Antineoplastic Agents Aromatase Inhibitors Attention Autopsy BRCA mutations Binding Binding Proteins Biochemical Biological Availability 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 Exclusion FLT3 gene FLT3 inhibition FLT3 inhibitor FRAP1 gene Fulvestrant Generations Genetic Transcription Goals Heart Hematologic Neoplasms Histology Hormones Hydrolase In Vitro Indiana Japan Lead Letrozole Liver Liver Microsomes Lung MEKs Malignant Neoplasms Mammary Neoplasms Maximum Tolerated Dose Mediating Medicine Mus Mutate Mutation Oncogenic Oncology Oral Organ Outcome PI3K/AKT Pathologic Pathway interactions Patients Pattern Permeability Pharmaceutical Preparations Pharmacologic Substance Phase I/II Clinical Trial Phase III Clinical Trials Phosphorylation Phosphotransferases Poly(ADP-ribose) Polymerase Inhibitor 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 biophysical properties cancer cell cancer therapy 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 pharmacologic pre-clinical protein kinase inhibitor quinoline refractory cancer resistance mechanism response scaffold scale up synergism triple-negative invasive breast carcinoma tumor growth

项目摘要

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.

项目概要：急性髓系白血病（AML）是一种毁灭性的癌症，尽管经过数十年的深入研究，选择有限。寻找治疗方法。 AML 的平均 5 年生存率约为 30%（对于所有患者），但对于大多数60岁以上的老年患者，2年生存率低于5%。大约 30% 的 AML 患者患有 FLT3 激酶突变，这些患者的结果最差。 Midostaurin 和 gilteritinib，FLT3 抑制剂分别于2017年和2018年获得批准。另一种 FLT3 抑制剂 Crenolanib 处于晚期 III 期临床试验，而 quizartinib 在日本获得批准，但未能获得 FDA 批准。然而，所有患者四种FLT3抑制剂最终因FLT3激酶的二次突变而复发（例如FLT3-ITD、D835 和F691突变体）和其他补偿性抵抗机制。乳腺癌平均5年 I 期和 II 期的生存率为 93%，但对于一小部分但显着比例 (15-20%) 的乳腺癌患者来说，对于患有激素难治性癌症（称为三阴性乳腺癌，TNBC）的人来说，治疗方法很少选项。显然，我们需要有效对抗 AML 和 TNBC 癌症的新疗法。 PI 已鉴定出新型 3H-吡唑并[4,3-f]喹啉基激酶抑制剂，仅在单个烧瓶中合成操作，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-吡唑并[4,3-f]喹啉核心的取代模式。涉及CDK12/13和CDK18 细胞对 DNA 损伤的反应以及这些激酶的抑制导致各种癌症中的 BRCA 性，使此类癌症对损伤 DNA 或抑制 DNA 损伤修复的药物（例如阿霉素）敏感或PARP抑制剂。该项目的总体目标是优化这些有趣的新类别激酶抑制剂可能转化为 AML 和乳腺治疗药物。在目标1中，第二代3H- 吡唑并[4,3-f]喹啉基化合物，（第一代化合物已经在体内表现出令人印象深刻的体内针对 AML 的功效），将在体内进行生化表征和评估（目标 3）。另外新的化学品将用于制造第三代 3H-吡唑并[4,3-f]喹啉基激酶抑制剂，该抑制剂具有更好的药物样特性。目标 2 描述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 细胞的效力对当前疗法（如gilteritinib）和三阴性乳腺癌细胞系具有耐药性的细胞系体外。在目标 3 中，PI 将评估先导化合物针对 AML 和乳腺肿瘤的体内功效。项目，针对 AML 和乳腺癌的新型药物，可抑制传统的 FLT3 (AML) 以及 CDK12/13 和 CDK18，它们是有趣的新癌症靶点，目前还没有针对它们的批准药物。