Targeting Metal-Dependent Epigenetic Modulators via MetalloPROTACs

通过 MetalloPROTAC 靶向金属依赖性表观遗传调节剂

基本信息

  • 批准号:
    10722294
  • 负责人:
  • 金额:
    $ 20.54万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary. While recent efforts have identified the need for methodologies capable of inactivating oncoproteins, current intervention strategies have left much of the proteome “undruggable.” In response the NCI has recognized this challenge as outlined in PAR-22-216 by incentivizing the development of new molecular targeting agents based on specific signaling pathways activated during the process of tumorigenesis or tumor progression. This program proposes an important next step in reaching these goals by providing a platform for the rapid development and characterization of heterobifunctional molecules capable of inducing degradation of cancer related metalloenzymes with new molecular targeting agents. In this program, our team will develop proteolysis targeting chimeras (PROTACs) containing state-of-the-art metal-binding pharmacophores (MBPs) with the ultimate goal of achieving isoform-selective degradation of jumonji C-domain containing lysine demethylases. Current strategies to inhibit conserved catalytic domain Jumonjis (JMJCs) involve targeting the α-ketoglutaric acid (2OG) substrate-accepting active site of JMJCs with inhibitors that can coordinate to the iron ion in the active site. Targeting the histone-binding helper domain of JMJCs generates additional isoform selectivity. However, no inhibitor has been shown to be selective for only one isoform of JMJCs. We have chosen to take a targeted degradation approach in order to increase the surface area of the peripheral interaction by recruiting an E3 ligase. This program will demonstrate how the potential protein- protein interaction induced by these chimeras can be leveraged to induce selective degradation of metalloproteins (`MetalloPROTACs') through rational MBP and linker design and will serve as a platform for the study of cancer biology, as well as laying the foundation for future development of therapeutic agents.
项目总结。虽然最近的努力已经确定需要能够使

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Michael D. Burkart其他文献

Data from mass spectrometry, NMR spectra, GC–MS of fatty acid esters produced by <em>Lasiodiplodia theobromae</em>
  • DOI:
    10.1016/j.dib.2016.05.003
  • 发表时间:
    2016-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Carla C. Uranga;Joris Beld;Anthony Mrse;Iván Córdova-Guerrero;Michael D. Burkart;Rufina Hernández-Martínez
  • 通讯作者:
    Rufina Hernández-Martínez
Reversal of malignant ADAR1 splice isoform switching with Rebecsinib
用 Rebecsinib 逆转恶性 ADAR1 剪接异构体转换
  • DOI:
    10.1016/j.stem.2023.01.008
  • 发表时间:
    2023-03-02
  • 期刊:
  • 影响因子:
    20.400
  • 作者:
    Leslie A. Crews;Wenxue Ma;Luisa Ladel;Jessica Pham;Larisa Balaian;S. Kathleen Steel;Phoebe K. Mondala;Raymond H. Diep;Christina N. Wu;Cayla N. Mason;Inge van der Werf;Isabelle Oliver;Eduardo Reynoso;Gabriel Pineda;Thomas C. Whisenant;Peggy Wentworth;James J. La Clair;Qingfei Jiang;Michael D. Burkart;Catriona H.M. Jamieson
  • 通讯作者:
    Catriona H.M. Jamieson
Gating mechanism of elongating β-ketoacyl-ACP synthases
延伸β-酮脂酰-ACP 合酶的门控机制
  • DOI:
    10.1038/s41467-020-15455-x
  • 发表时间:
    2020-04-07
  • 期刊:
  • 影响因子:
    15.700
  • 作者:
    Jeffrey T. Mindrebo;Ashay Patel;Woojoo E. Kim;Tony D. Davis;Aochiu Chen;Thomas G. Bartholow;James J. La Clair;J. Andrew McCammon;Joseph P. Noel;Michael D. Burkart
  • 通讯作者:
    Michael D. Burkart
The Complete Characterization of a Trapped ACYL Carrier Protein-Ketosynthase Complex
  • DOI:
    10.1016/j.bpj.2019.11.1114
  • 发表时间:
    2020-02-07
  • 期刊:
  • 影响因子:
  • 作者:
    Jeffrey T. Mindrebo;Laetitia E. Misson;Ashay Patel;Katia Charov;Joseph P. Noel;Michael D. Burkart
  • 通讯作者:
    Michael D. Burkart
Crosslinking intermodular condensation in non-ribosomal peptide biosynthesis
非核糖体肽生物合成中的交联模块间缩合
  • DOI:
    10.1038/s41586-024-08306-y
  • 发表时间:
    2024-12-11
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Graham W. Heberlig;James J. La Clair;Michael D. Burkart
  • 通讯作者:
    Michael D. Burkart

Michael D. Burkart的其他文献

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{{ truncateString('Michael D. Burkart', 18)}}的其他基金

Enabling synthetic biology through single cell functional genomics
通过单细胞功能基因组学实现合成生物学
  • 批准号:
    10556421
  • 财政年份:
    2022
  • 资助金额:
    $ 20.54万
  • 项目类别:
Chemistry-Biology Interfaces at UCSD
加州大学圣地亚哥分校的化学-生物学接口
  • 批准号:
    10652649
  • 财政年份:
    2022
  • 资助金额:
    $ 20.54万
  • 项目类别:
Human mitochondrial ACP interactions
人类线粒体 ACP 相互作用
  • 批准号:
    10469436
  • 财政年份:
    2021
  • 资助金额:
    $ 20.54万
  • 项目类别:
Human mitochondrial ACP interactions
人类线粒体 ACP 相互作用
  • 批准号:
    10286779
  • 财政年份:
    2021
  • 资助金额:
    $ 20.54万
  • 项目类别:
Splice modulatory therapy for valley fever
谷热的剪接调节疗法
  • 批准号:
    10042570
  • 财政年份:
    2020
  • 资助金额:
    $ 20.54万
  • 项目类别:
Targeting protein-protein interactions as drug targets
将蛋白质-蛋白质相互作用作为药物靶点
  • 批准号:
    10306398
  • 财政年份:
    2020
  • 资助金额:
    $ 20.54万
  • 项目类别:
Chemical Biology Interfaces at UC San Diego
加州大学圣地亚哥分校的化学生物学接口
  • 批准号:
    9064164
  • 财政年份:
    2015
  • 资助金额:
    $ 20.54万
  • 项目类别:
Chemical Biology Interfaces at UC San Diego
加州大学圣地亚哥分校的化学生物学接口
  • 批准号:
    8794193
  • 财政年份:
    2015
  • 资助金额:
    $ 20.54万
  • 项目类别:
Protein-Protein Interactions in Natural Product Biosynthesis
天然产物生物合成中的蛋白质-蛋白质相互作用
  • 批准号:
    10249686
  • 财政年份:
    2012
  • 资助金额:
    $ 20.54万
  • 项目类别:
Protein-Protein Interactions in Natural Product Biosynthesis
天然产物生物合成中的蛋白质-蛋白质相互作用
  • 批准号:
    10548747
  • 财政年份:
    2012
  • 资助金额:
    $ 20.54万
  • 项目类别:

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