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Methods and approaches to expand the pharmacological toolset

扩展药理学工具集的方法和途径

基本信息

批准号：
10678871
负责人：
Michael J Bollong
金额：
$ 45.25万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2022-08-15 至 2027-06-30
项目状态：
未结题

项目摘要

Project summary Our laboratory identifies small molecules with physiological activity to advance biological discovery and to develop new medicines. The principal goal of this R35 early-stage investigator MIRA proposal will be to enable our research effort collectively, which we believe will be best maximized by focusing on three key areas. In the first, we have been advancing multiple pharmacological approaches in the field of regenerative medicine. Here, we have developed a unique toolset to promote regenerative tissue repair, targeting the Hippo YAP pathway as well as multiple tissue resident stem cell populations. We will continue to augment this toolset, delineating knowledge about the signaling logic of these pathways and identifying key mechanisms that can be potentially exploited therapeutically, as we have done to date. Second, we have significant efforts in ‘liganding’ the roughly twenty transcriptional responses to cellular stress, including heat shock, oxidative, proteostasis, among others. We have developed best in class activators of the NRF2 pathway and have shown superiority to the clinical stage molecule Bardoxolone methyl in animal models. Likewise, we have used chemical tools to understand the essential language of how central carbon metabolism ‘talks’ to the oxidative stress sensing machinery of the cell. We will continue to develop novel small molecules for targeting these largely unliganded transcriptional responses. Lastly, we will continue developing novel methods to effectively mine screening libraries for small molecules with interesting and useful properties. We are developing methods to effectively screen libraries for new covalent reactive groups as well as developing new methodology to screen enzyme families en masse.

项目总结

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A covalent inhibitor of the YAP-TEAD transcriptional complex identified by high-throughput screening.

DOI：
10.1039/d3cb00044c
发表时间：
2023-11-01
期刊：
RSC chemical biology
影响因子：
4.1
作者：
通讯作者：

S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite activates NRF2 signaling.

DOI：
10.1073/pnas.2300763120
发表时间：
2023-05-16
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Ko, Yeonjin;Hong, Mannkyu;Lee, Seungbeom;Kumar, Manoj;Ibrahim, Lara;Nutsch, Kayla;Stanton, Caroline;Sandoval, Braddock;Sondermann, Phillip;Bulos, Maya L.;Iaconelli, Jonathan;Chatterjee, Arnab K.;Wiseman, R. Luke;Schultz, Peter G.;Bollong, Michael J.
通讯作者：
Bollong, Michael J.

Pharmacological YAP activation promotes regenerative repair of cutaneous wounds.

药理学YAP激活促进皮肤伤口的再生修复。

DOI：
10.1073/pnas.2305085120
发表时间：
2023-07-11
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Grzelak, Edyta M.;Elshan, N. G. R. Dayan;Shao, Sida;Bulos, Maya L.;Joseph, Sean B.;Chatterjee, Arnab K.;Chen, Jian Jeffrey;Nguyen-Tran, Van;Schultz, Peter G.;Bollong, Michael J.
通讯作者：
Bollong, Michael J.

A high throughput screen for pharmacological inhibitors of the carbohydrate response element.

DOI：
10.1038/s41597-023-02596-z
发表时间：
2023-10-04
期刊：
SCIENTIFIC DATA
影响因子：
9.8
作者：
You, Shaochen;Bollong, Michael J.
通讯作者：
Bollong, Michael J.

Optimization of 3-aminotetrahydrothiophene 1,1-dioxides with improved potency and efficacy as non-electrophilic antioxidant response element (ARE) activators.

优化 3-氨基四氢噻吩 1,1-二氧化物，提高作为非亲电子抗氧化反应元件 (ARE) 激活剂的效力和功效。

DOI：
10.1016/j.bmcl.2023.129306
发表时间：
2023
期刊：
Bioorganic & medicinal chemistry letters
影响因子：
2.7
作者：
Jo,Jeyun;Kim,Jisu;Ibrahim,Lara;Kumar,Manoj;Iaconelli,Jonathan;Tran,CongSo;Moon,HyungRyong;Jung,Yunjin;Wiseman,RLuke;Lairson,LukeL;Chatterjee,ArnabK;Bollong,MichaelJ;Yun,Hwayoung
通讯作者：
Yun,Hwayoung