Discovery of a Novel Pseudo‐Natural Product Aurora Kinase Inhibitor Chemotype through Morphological Profiling

Author:

Wang Lin1,Yilmaz Furkan12,Yildirim Okan1,Schölermann Beate1,Bag Sukdev1,Greiner Luca1,Pahl Axel13ORCID,Sievers Sonja13ORCID,Scheel Rebecca4,Strohmann Carsten4ORCID,Squire Christopher5,Foley Daniel J.6,Ziegler Slava1ORCID,Grigalunas Michael1ORCID,Waldmann Herbert12ORCID

Affiliation:

1. Department of Chemical Biology Max Planck Institute of Molecular Physiology 44227 Dortmund Germany

2. Faculty of Chemistry and Chemical Biology TU Dortmund University 44227 Dortmund Germany

3. Compound Management and Screening Center (COMAS) 44227 Dortmund Germany

4. Faculty of Chemistry and Inorganic Chemistry TU Dortmund University 44227 Dortmund Germany

5. School of Biological Sciences University of Auckland 1142 Auckland New Zealand

6. School of Physical and Chemical Sciences University of Canterbury 8041 Christchurch New Zealand

Abstract

AbstractThe pseudo‐natural product (pseudo‐NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. The resulting compounds retain the biological relevance of NPs but are not yet linked to bioactivities and may therefore be best evaluated by unbiased screening methods resulting in the identification of unexpected or unprecedented bioactivities. Herein, various NP fragments are combined with a tricyclic core connectivity via interrupted Fischer indole and indole dearomatization reactions to provide a collection of highly three‐dimensional pseudo‐NPs. Target hypothesis generation by morphological profiling via the cell painting assay guides the identification of an unprecedented chemotype for Aurora kinase inhibition with both its relatively highly 3D structure and its physicochemical properties being very different from known inhibitors. Biochemical and cell biological characterization indicate that the phenotype identified by the cell painting assay corresponds to the inhibition of Aurora kinase B.

Funder

European Commission

Innovative Medicines Initiative

Seventh Framework Programme

Publisher

Wiley

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3