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:
  • 金额:
    $ 45.22万
  • 依托单位:
  • 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

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: 急性髓性白血病(AML)是一种毁灭性的癌症,尽管数十年来一直在进行密集的治疗,但选择有限。 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 大多数60岁以上的老年患者,2年生存率不到5%。大约30%的AML患者 突变的FLT 3激酶,这些患者的预后最差。米多替尼和gilteritinib,FLT 3抑制剂 分别于二零一七年及二零一八年获批准。另一种FLT 3抑制剂Crenolanib处于III期临床晚期 Quizartinib在日本获得批准,但未能获得FDA批准。然而,所有患者 四种FLT 3抑制剂由于FLT 3激酶的继发性突变(如FLT 3-ITD,D835 和F691突变体)和其它补偿抗性机制。乳腺癌平均5年 I期和II期的存活率为93%,但对于较小但显著百分比(15-20%)的乳腺癌患者, 对于患有激素难治性癌症(称为三阴性乳腺癌,TNBC)的人,很少有治疗方法。 选项.显然,需要对AML和TNBC癌症有效的新疗法。法律与正义党 已经鉴定了仅在单个烧瓶中合成的新型3 H-吡唑并[4,3-f]喹啉基激酶抑制剂 有效抑制FLT 3和/或CDK 2或CDK 12/13或CDK 18。这些激酶的选择性 取决于3 H-吡唑并[4,3-f]喹啉核的取代模式。CDK 12/13和CDK 18参与 在细胞对DNA损伤的反应中,这些激酶的抑制导致各种癌症中的BRCAness, 使这类癌症对损伤DNA或抑制DNA损伤修复的试剂敏感,如阿霉素 或PARP抑制剂。这个项目的总体目标是优化这些有趣的新类, 激酶抑制剂,用于可能转化为AML和乳腺治疗剂。在目标1中,第二代3 H- 吡唑并[4,3-f]喹啉类化合物(第一代化合物已经显示出令人印象深刻的体内 体内抗AML的功效),将在体内进行生物化学表征和评价(目的3)。新增 化学将用于制造第三代3 H-吡唑并[4,3-f]喹啉基激酶抑制剂, 更好的药物性质。目的2:研究这些新的有效抗增殖化合物如何影响蛋白质 本发明的目的是为了测定化合物在癌细胞中的磷酸化并测定化合物杀死各种AML细胞的效力, 对目前的治疗如gilteritinib具有抗性的细胞系,以及 体外在目标3中,PI将评价先导化合物对AML和乳腺肿瘤的体内疗效。 项目,针对AML和乳腺癌的新型药物,抑制传统的FLT 3(AML)以及CDK 12/13 和CDK 18,它们是有趣的新癌症靶点,没有批准的靶向药物。

项目成果

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Reuben Kapur其他文献

Reuben Kapur的其他文献

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{{ truncateString('Reuben Kapur', 18)}}的其他基金

Dual anti-leukemic and cardio protective role for ROCK
ROCK的双重抗白血病和心脏保护作用
  • 批准号:
    10435743
  • 财政年份:
    2022
  • 资助金额:
    $ 45.22万
  • 项目类别:
Dual anti-leukemic and cardio protective role for ROCK
ROCK的双重抗白血病和心脏保护作用
  • 批准号:
    10597132
  • 财政年份:
    2022
  • 资助金额:
    $ 45.22万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 45.22万
  • 项目类别:
Novel drug to treat poor prognosis AML
治疗预后不良的 AML 的新药
  • 批准号:
    10290199
  • 财政年份:
    2021
  • 资助金额:
    $ 45.22万
  • 项目类别:
Novel drug to treat poor prognosis AML
治疗预后不良的 AML 的新药
  • 批准号:
    10443887
  • 财政年份:
    2021
  • 资助金额:
    $ 45.22万
  • 项目类别:
Hyperglycemia mediated myeloproliferative disease
高血糖介导的骨髓增生性疾病
  • 批准号:
    9899320
  • 财政年份:
    2019
  • 资助金额:
    $ 45.22万
  • 项目类别:
Hyperglycemia mediated myeloproliferative disease
高血糖介导的骨髓增生性疾病
  • 批准号:
    10386813
  • 财政年份:
    2019
  • 资助金额:
    $ 45.22万
  • 项目类别:
Targeting Novel Pathways in JMML
针对 JMML 中的新途径
  • 批准号:
    10324564
  • 财政年份:
    2019
  • 资助金额:
    $ 45.22万
  • 项目类别:
Targeting Novel Pathways in JMML
针对 JMML 中的新途径
  • 批准号:
    10077886
  • 财政年份:
    2019
  • 资助金额:
    $ 45.22万
  • 项目类别:
Hyperglycemia mediated myeloproliferative disease
高血糖介导的骨髓增生性疾病
  • 批准号:
    9765447
  • 财政年份:
    2019
  • 资助金额:
    $ 45.22万
  • 项目类别:
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