Phosphodiesterase 10A, a novel target for lung cancer chemoprevention
磷酸二酯酶10A,肺癌化学预防的新靶点
基本信息
- 批准号:10456469
- 负责人:
- 金额:$ 26.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-23 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Abstract
Preclinical, clinical and epidemiological studies provide compelling evidence that
nonsteroidal anti-inflammatory drugs (NSAIDs) have antineoplastic activity and significantly
reduce the incidence and risk of death from multiple cancer types, including lung cancer.
Unfortunately, the long-term use of NSAIDs for chemoprevention and their potential application
for therapy are not recommended because of the risk of potentially fatal side-effects resulting
from cyclooxygenase (COX) inhibition and the suppression of physiologically important
prostaglandins. However, numerous investigators have concluded that the pharmacological
basis for their antineoplastic activity may not require COX inhibition, which suggests the
feasibility of developing safer and more efficacious non-COX inhibitory derivatives for cancer by
targeting the underlying mechanism. We have extensively studied the mechanism by which the
NSAID, sulindac inhibits tumor cell growth and have reported that this activity results from cyclic
guanosine monophosphate phosphodiesterase (cGMP PDE) inhibition and the activation of
cGMP/protein kinase G signaling to suppress oncogenic β-catenin/Tcf-transcriptional activity
and the synthesis of key proteins, such as cyclin D1 and survivin that drive tumor cell
proliferation and survival. Here we show that the cGMP degrading PDE isozyme, PDE10A is a
critically important target of sulindac that is elevated in lung tumors and essential for lung tumor
cell growth. Guided by molecular modeling using the crystal structure of PDE10, we synthesized
a novel series of sulindac derivatives that potently and selectively inhibit lung tumor cell growth
without inhibiting COX-1 or COX-2. These compounds have attractive drug-like properties
whereby high lung concentrations relative to plasma and other tissues can be safely achieved
by oral administration. A lead compound, MCI-048 was identified that displays strong antitumor
activity in an orthotopic mouse model of lung cancer. Further analog development to identify a
preclinical drug development candidate and studies to better define the role of PDE10 in lung
cancer are therefore urgently needed. The following aims are proposed: 1) synthesize a novel
series of sulindac derivatives to improve potency and selectivity, 2) evaluate PDE10 and lung
tumor cell growth inhibitory activity of sulindac derivatives, 3) evaluate antitumor activity of
sulindac derivatives in mouse models of lung cancer, and 4) further define the role of PDE10 in
lung cancer. The focus of this project on the development of novel anticancer drugs and target
validation for chemoprevention or therapy have the potential to impact individuals at risk of
developing lung cancer as well as patients with advanced stage malignant disease.
摘要
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The RAS-Effector Interaction as a Drug Target.
RAS-效应器相互作用作为药物靶点。
- DOI:10.1158/0008-5472.can-16-0938
- 发表时间:2017-01-15
- 期刊:
- 影响因子:11.2
- 作者:Keeton AB;Salter EA;Piazza GA
- 通讯作者:Piazza GA
Suppression of β-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10.
- DOI:10.18632/oncotarget.4741
- 发表时间:2015-09-29
- 期刊:
- 影响因子:0
- 作者:Li N;Chen X;Zhu B;Ramírez-Alcántara V;Canzoneri JC;Lee K;Sigler S;Gary B;Li Y;Zhang W;Moyer MP;Salter EA;Wierzbicki A;Keeton AB;Piazza GA
- 通讯作者:Piazza GA
Discovery of trisubstituted pyrazolines as a novel scaffold for the development of selective phosphodiesterase 5 inhibitors.
- DOI:10.1016/j.bioorg.2020.104322
- 发表时间:2020-11
- 期刊:
- 影响因子:5.1
- 作者:Abdel-Halim M;Tinsley H;Keeton AB;Weam M;Atta NH;Hammam MA;Hefnawy A;Hartmann RW;Engel M;Piazza GA;Abadi AH
- 通讯作者:Abadi AH
Sulindac sulfide selectively increases sensitivity of ABCC1 expressing tumor cells to doxorubicin and glutathione depletion.
- DOI:10.7555/jbr.30.20150108
- 发表时间:2016-03
- 期刊:
- 影响因子:2.3
- 作者:Whitt JD;Keeton AB;Gary BD;Sklar LA;Sodani K;Chen ZS;Piazza GA
- 通讯作者:Piazza GA
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Gary A Piazza其他文献
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{{ truncateString('Gary A Piazza', 18)}}的其他基金
Novel inhibitor for oncogenic RAS for lung cancer
肺癌致癌 RAS 的新型抑制剂
- 批准号:
10312820 - 财政年份:2021
- 资助金额:
$ 26.74万 - 项目类别:
Novel inhibitor for oncogenic RAS for lung cancer
肺癌致癌 RAS 的新型抑制剂
- 批准号:
10664823 - 财政年份:2021
- 资助金额:
$ 26.74万 - 项目类别:
Novel inhibitor for oncogenic RAS for lung cancer
肺癌致癌 RAS 的新型抑制剂
- 批准号:
10408381 - 财政年份:2021
- 资助金额:
$ 26.74万 - 项目类别:
Exploiting the immunomodulatory effects of sulindac and novel non-COX inhibitory derivatives for cancer treatment
利用舒林酸和新型非 COX 抑制衍生物的免疫调节作用来治疗癌症
- 批准号:
10113565 - 财政年份:2020
- 资助金额:
$ 26.74万 - 项目类别:
Exploiting the immunomodulatory effects of sulindac and novel non-COX inhibitory derivatives for cancer treatment
利用舒林酸和新型非 COX 抑制衍生物的免疫调节作用来治疗癌症
- 批准号:
9917342 - 财政年份:2020
- 资助金额:
$ 26.74万 - 项目类别:
Exploiting the immunomodulatory effects of sulindac and novel non-COX inhibitory derivatives for cancer treatment
利用舒林酸和新型非 COX 抑制衍生物的免疫调节作用来治疗癌症
- 批准号:
10360574 - 财政年份:2020
- 资助金额:
$ 26.74万 - 项目类别:
Exploiting the immunomodulatory effects of sulindac and novel non-COX inhibitory derivatives for cancer treatment
利用舒林酸和新型非 COX 抑制衍生物的免疫调节作用来治疗癌症
- 批准号:
10594951 - 财政年份:2020
- 资助金额:
$ 26.74万 - 项目类别:
Phosphodiesterase 10A, a novel target for lung cancer chemoprevention
磷酸二酯酶10A,肺癌化学预防的新靶点
- 批准号:
9198369 - 财政年份:2016
- 资助金额:
$ 26.74万 - 项目类别:
Phosphodiesterase 10A, a novel target for lung cancer chemoprevention
磷酸二酯酶10A,肺癌化学预防的新靶点
- 批准号:
9316610 - 财政年份:2016
- 资助金额:
$ 26.74万 - 项目类别:
Phosphodiesterase 10A, a novel target for lung cancer chemoprevention
磷酸二酯酶10A,肺癌化学预防的新靶点
- 批准号:
9904554 - 财政年份:2016
- 资助金额:
$ 26.74万 - 项目类别:
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背侧纹状体磷酸二酯酶 10A 和强迫性乙醇使用
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10660892 - 财政年份:2021
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$ 26.74万 - 项目类别:
Phosphodiesterase 10A, a novel target for lung cancer chemoprevention
磷酸二酯酶10A,肺癌化学预防的新靶点
- 批准号:
9198369 - 财政年份:2016
- 资助金额:
$ 26.74万 - 项目类别:
Phosphodiesterase 10A, a novel target for lung cancer chemoprevention
磷酸二酯酶10A,肺癌化学预防的新靶点
- 批准号:
9316610 - 财政年份:2016
- 资助金额:
$ 26.74万 - 项目类别:
Phosphodiesterase 10A, a novel target for lung cancer chemoprevention
磷酸二酯酶10A,肺癌化学预防的新靶点
- 批准号:
9904554 - 财政年份:2016
- 资助金额:
$ 26.74万 - 项目类别:
DEVELOPING PET AGENTS FOR IMAGING PHOSPHODIESTERASE 10A (PDE10A)
开发用于磷酸二酯酶 10A (PDE10A) 成像的宠物试剂
- 批准号:
8551075 - 财政年份:2011
- 资助金额:
$ 26.74万 - 项目类别:
DEVELOPING PET AGENTS FOR IMAGING PHOSPHODIESTERASE 10A (PDE10A)
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DEVELOPING PET AGENTS FOR IMAGING PHOSPHODIESTERASE 10A (PDE10A)
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8661060 - 财政年份:2011
- 资助金额:
$ 26.74万 - 项目类别:
DEVELOPING PET AGENTS FOR IMAGING PHOSPHODIESTERASE 10A (PDE10A)
开发用于磷酸二酯酶 10A (PDE10A) 成像的宠物试剂
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8033025 - 财政年份:2011
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