Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3β

Wang, Yikai; Wach, Jean Yves; Sheehan, Patrick; Zhong, Cheng; Zhan, Changhong; Harris, Richard; Almo, Steven C.; Bishop, Joshua; Haggarty, Stephen J.; Ramek, Alexander; Berry, Kayla N.; O’Herin, Conor; Koehler, Angela N.; Hung, Alvin W.; Young, Damian W.

doi:10.1021/acsmedchemlett.6b00230

Cited by 35 publications

(21 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The examples shown in Figure 1 illustrate how the interrogation of compound libraries synthesized using DOS and related strategies has afforded small-molecule bioactives across a wide range of heritable diseases (defined here as diseases that may be influenced by heritable genetic characteristics); 71–82 notably absent are compounds for the study of genetic targets in cancer, which will be discussed in a separate section. Here, we highlight three vignettes that provide greater insight into the underlying synthetic pathways, compound libraries, and chemical biology.…”

Section: Probes For Heritable Disease Targetsmentioning

confidence: 99%

Chemical probes and drug leads from advances in synthetic planning and methodology

Gerry

Schreiber

2018

Nat Rev Drug Discov

208

164

View full text Add to dashboard Cite

Screening of small-molecule libraries is a productive method for identifying both chemical probes of disease-related targets and potential starting points for drug discovery. In this article, we focus on strategies such as diversity-oriented synthesis that aim to explore novel areas of chemical space efficiently by populating small-molecule libraries with compounds containing structural features that are typically under-represented in commercially available screening collections. Drawing from more than a decade's worth of examples, we highlight how the design and synthesis of such libraries have been enabled by modern synthetic chemistry, and we illustrate the impact of the resultant chemical probes and drug leads in a wide range of diseases.

show abstract

Section: Probes For Heritable Disease Targetsmentioning

confidence: 99%

Chemical probes and drug leads from advances in synthetic planning and methodology

Gerry

Schreiber

2018

Nat Rev Drug Discov

208

164

View full text Add to dashboard Cite

show abstract

“…[1][2][3][4][5][6][7] The production of these libraries allows for the analysis of structure-activity relationships of the compounds, which helps inform further development of probes with diverse activity. [8][9][10][11][12][13][14][15][16] Biological performance diversity can be defined as the ability of a compound library to target a broad variety of biological functions, while containing few molecules with redundant activity. Such libraries more efficiently use resources, due to a smaller library footprint, while potentially increasing hit rates.…”

Section: Introductionmentioning

confidence: 99%

Multiple Chemical Features Impact Biological Performance Diversity of a Highly Active Natural Product‐Inspired Library

et al. 2020

View full text Add to dashboard Cite

A systematic, diversity-oriented synthesis approach was employed to access a natural product-inspired flavonoid library with diverse chemical features, including chemical properties, scaffold, stereochemistry, and appendages. Using Cell Painting, the effects of these diversity elements were evaluated, and multiple chemical features that predict biological performance diversity were identified. Scaffold identity appears to be the dominant predictor of performance diversity, but stereochemis-try and appendages also contribute to a lesser degree. In addition, the diversity of chemical properties contributed to performance diversity, and the driving chemical property was dependent on the scaffold. These results highlight the importance of key chemical features that may inform the creation of small-molecule, performance-diverse libraries to improve the efficiency and success of high-throughput screening campaigns.

show abstract

“…Finally, Young and co-workers recently demonstrated the successful use of the DOS strategy to optimize fragments against the serine/theronine kinase GSK3β (Wang et al, 2016 ), which is overexpressed in cancer and Alzheimer's disease (Luo, 2009 ; Hernandez et al, 2012 ). To initiate the investigation, a set of 86 fragments was compiled from DOS libraries constructed via three distinct B/C/P pathways (Figure 2E ).…”

Section: Demonstration Of Dos Methodologies For the Identification Ofmentioning

confidence: 99%

“…(D) Foley et al ( 2017 ) synthesis of scaffolds distantly related to natural products. (E) Wang et al ( 2016 ) DOS fragment evolution strategy against GSK3.…”

Section: The Application Of Dos To Access Novel Fragments With Multipmentioning

confidence: 99%

Recent Applications of Diversity-Oriented Synthesis Toward Novel, 3-Dimensional Fragment Collections

et al. 2018

View full text Add to dashboard Cite

Fragment-based drug discovery (FBDD) is a well-established approach for the discovery of novel medicines, illustrated by the approval of two FBBD-derived drugs. This methodology is based on the utilization of small “fragment” molecules (<300 Da) as starting points for drug discovery and optimization. Organic synthesis has been identified as a significant obstacle in FBDD, however, in particular owing to the lack of novel 3-dimensional (3D) fragment collections that feature useful synthetic vectors for modification of hit compounds. Diversity-oriented synthesis (DOS) is a synthetic strategy that aims to efficiently produce compound collections with high levels of structural diversity and three-dimensionality and is therefore well-suited for the construction of novel fragment collections. This Mini-Review highlights recent studies at the intersection of DOS and FBDD aiming to produce novel libraries of diverse, polycyclic, fragment-like compounds, and their application in fragment-based screening projects.

show abstract

Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3β

Cited by 35 publications

References 34 publications

Chemical probes and drug leads from advances in synthetic planning and methodology

Chemical probes and drug leads from advances in synthetic planning and methodology

Multiple Chemical Features Impact Biological Performance Diversity of a Highly Active Natural Product‐Inspired Library

Recent Applications of Diversity-Oriented Synthesis Toward Novel, 3-Dimensional Fragment Collections

Contact Info

Product

Resources

About