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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：
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
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/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

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.

项目总结: