课题基金 / 基金详情

Development of PARP-Isoform Selective Inhibitory Chemical Probes

Development of PARP-Isoform Selective Inhibitory Chemical Probes
PARP-异构体选择性抑制化学探针的开发
批准号:
10437639
负责人:
Tanaji T Talele
金额:
$12.3万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-07-03 至 2024-06-30

项目摘要

项目成果

Tanaji T Talele的其他基金

相似基金

相关文献

中文摘要
翻译
项目总结/文摘
英文摘要
Project Summary/Abstract The development of highly isoform-selective poly(ADP-ribose) polymerase (PARP) biochemical probes will fill crucial knowledge gaps that exist in our understanding of biological functions of PARP enzymes. PARPs are a family of nuclear enzymes that catalyze poly(ADP-ribosyl)ation (PARylation) of substrate proteins such as histones. PARylation facilitates recruitment of DNA repair proteins. Consequently, PARP inhibitors (PARPi) are developed as a novel class of anticancer drugs that are used as single agents to treat BRCA-deficient tumors and as combination therapy with DNA damaging agents. The PARP superfamily is comprised of 17 members. Clinical PARPi are often associated with promiscuous inhibition of both PARP-1 and PARP-2 and some of them even inhibit other PARPs. This becomes a potential cause for their off-target hematologic toxicity. Due to non- specific targeting of multiple PARP-isoforms by currently known PARPi, a thorough interpretation of their pharmacological/clinical profiles has become highly complex. Further it was shown that PARP-1 inhibition alone is sufficient to repress the growth of MDA-MB-436 tumor xenograft. Depletion of both PARP-1 and PARP-2 led to embryonic lethality and aggressive T-cell lymphomas. One of the challenges impeding evaluation of PARP- isoform specific molecular interaction landscape in cellular context is the lack of potent and highly PARP-isoform selective chemical probes. Therefore, development of highly isoform selective PARP inhibitory probes is urgently needed. Weplan to address this by developing isoform-selective and potentially non-toxic novel PARP inhibitory chemical probes that will allow interrogation of changes in downstream signaling events of individual PARPs at a molecular level. The probes generated herein will also serve as template for the next generation preclinical agents. We will apply highly potent and novel set of UTT-lead compounds to develop exquisitely PARP-isoform selective chemical probes that will facilitate our understanding of biological functions of individual PARPs in both normal and diseased cells. As a proof-of-concept, we have synthesized and characterized several PARPi with nanomolar potency against both PARP-1 and PARP-2, with ~30-fold higher preference toward PARP-2. Based on this scientific premise and preliminary data, we propose the following specific aims: (A) to identify PARP-1 and PARP-2 selective biochemical probes; (B) to conduct in vitro PARP enzyme assays and isoform selectivity screening, and (C) to evaluate cytotoxicity of an isoform selective best PARPi in CAPAN-1 (BRCA2-/- and BRCA2cor) and SUM149 (BRCA1-/- and BRCA1cor) cells. These studies are expected to expand our knowledge on the impact of inhibiting a specific PARP-isoform by developed PARP chemical probes. By the end of the grant project period, we will be poised to evaluate cell-active and highly PARP-selective chemical probes in high value cell-based experiments. Subsequently, we plan to investigate PARP-isoform specific downstream signaling events, identification of new PARylated substrate proteins, on-target engagement and phenotypic change, and to validate if other PARPs are viable pharmacological targets.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1038/s41556-021-00807-6
发表时间: 2022-01
期刊: Nature cell biology
影响因子: 21.3
作者: [Krastev DB, Li S, Sun Y, Wicks AJ, Hoslett G, Weekes D, Badder LM, Knight EG, Marlow R, Pardo MC, Yu L, Talele TT, Bartek J, Choudhary JS, Pommier Y, Pettitt SJ, Tutt ANJ, Ramadan K, Lord CJ]
通讯作者: Lord CJ
DOI: 10.1016/j.bioorg.2020.104075
发表时间: 2020-09
期刊: Bioorganic chemistry
影响因子: 5.1
作者: [Shao X, Pak S, Velagapudi UK, Gobbooru S, Kommaraju SS, Low WK, Subramaniam G, Pathak SK, Talele TT]
通讯作者: Talele TT
Development of PARP-Isoform Selective Inhibitory Chemical Probes
  • 批准号:
    10171867
  • 项目类别:
  • 资助金额:
    $12.3万
  • 财政年份:
    2019
  • 负责人:
    Tanaji T Talele
  • 依托单位:
海外基金