Design and Synthesis of Protein Superfamily-Targeted Chemical Libraries for Lead Identification and Optimization

Shuttleworth, Stephen J.; Connors, Richard; Fu, Jiasheng; Liu, Jinqian; Lizarzaburu, Mike E.; Qiu, Wei; Sharma, Rajiv; Wanska, Malgorzata; Zhang, Alex J.

doi:10.2174/0929867054020936

Cited by 24 publications

(11 citation statements)

References 227 publications

(303 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Focused and targeted combinatorial libraries have gained an increased interest in recent years (35)(36)(37). The core scaffolds presented here represent potential starting points of focused or targeted combinatorial libraries.…”

Section: Discussionmentioning

confidence: 99%

Increased Diversity of Libraries from Libraries: Chemoinformatic Analysis of Bis‐Diazacyclic Libraries

et al. 2011

View full text Add to dashboard Cite

Combinatorial libraries continue to play a key role in drug discovery. To increase structural diversity, several experimental methods have been developed. However, limited efforts have been performed so far to quantify the diversity of the broadly used diversity-oriented synthetic (DOS) libraries. Herein we report a comprehensive characterization of 15 bis-diazacyclic combinatorial libraries obtained through libraries from libraries, which is a DOS approach. Using MACCS keys, radial and different pharmacophoric fingerprints as well as six molecular properties, it was demonstrated the increased structural and property diversity of the libraries from libraries over the individual libraries. Comparison of the libraries to existing drugs, NCI Diversity and the Molecular Libraries Small Molecule Repository revealed the structural uniqueness of the combinatorial libraries (mean similarity < 0.5 for any fingerprint representation). In particular, biscyclic thiourea libraries were the most structurally dissimilar to drugs retaining drug-like character in property space. This study represents the first comprehensive quantification of the diversity of libraries from libraries providing a solid quantitative approach to compare and contrast the diversity of DOS libraries with existing drugs or any other compound collection.

show abstract

Section: Discussionmentioning

confidence: 99%

Increased Diversity of Libraries from Libraries: Chemoinformatic Analysis of Bis‐Diazacyclic Libraries

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Another approach, applicable to protein interactions at large, would consist in trying to define generic chemical spaces populated by small-molecules that would be more susceptible than others to inhibit protein interactions in general. The definition and use of such focused libraries has proved useful for some classes of therapeutic targets, such as protein kinases or GPCRs [61]. As the structural knowledge of protein complexes and the list of protein interaction inhibitors will grow at an accelerating pace, future will tell whether protein binding interfaces and small-molecule inhibitors share enough structural and biophysical determinants to allow the definition of chemical libraries focused on protein interactions [62].…”

Section: Resultsmentioning

confidence: 99%

High-Throughput Screening Assays to Discover Small-Molecule Inhibitors of Protein Interactions

Colas

2008

CDDT

View full text Add to dashboard Cite

The availability of large collections of small-molecule inhibitors of protein interactions would bear a tremendous impact both on academic and therapeutic research. The past recent years have seen a marked acceleration in the discovery of protein interaction inhibitors, through structure-based drug design but mostly through screening efforts. This article attempts to review the impressive number and variety of in vitro and cellular screening assays that have been developed and, for most of them, used successfully to identify small-molecule inhibitors of protein interactions. Various strategies aimed at improving hit rates are also reviewed, and future challenges to improve discovery success rates are discussed. The growing list of protein interaction inhibitors and the large arsenal of screening methods, now available to most laboratories or screening facilities, will probably convince an increasing number of academic and industrial scientists that protein interactions are more druggable than once feared, and that their respective research interests would greatly benefit from the discovery of protein interaction inhibitors.

show abstract

“…There are two broad means by which the library can be created. One consists of parallel synthesis where combinatorial chemistry is employed to make a library consisting of a superfamily of molecules [56]. The advantages of this approach is that a very large library could be rapidly generated, and identified hits could be amenable to subsequent chemical modification aimed at refining their properties.…”

Section: The Design Of Small Molecule Librarymentioning

confidence: 99%

Small Molecule Inhibitors of the Prolactin Receptor in Breast Cancer

Jacobson¹,

Papoian²,

Ben‐Jonathan³

2010

TOPROCJ

View full text Add to dashboard Cite

Breast cancer is both a common and a significant health concern for women across the globe. Emerging evidence suggests that the prolactin (PRL) signaling cascade contributes to the pathophysiology of breast cancer as well as to chemoresistance. The importance of this pathway to breast cancer has been elucidated by in vitro studies, genetic manipulations in mice, and case control analyses in human populations. To date, a number of different strategies, none of which have yet made it to the clinical stage, have been advanced as a means for blocking the PRL receptor (PRLR). This paper presents the rationale and strategy for the development of novel small molecule competitive antagonists of the PRLR as a therapeutics in breast cancer. It is predicted that the future of breast cancer treatment will continue to evolve and will be different than what it is today. Combination therapies will be applied that will concurrently target multiple molecules of interest. Novel small molecules will be employed as a means to turn off the PRL signaling pathway in breast cancer cells. Different molecules may well be applied to different genotypic individuals on the basis of the polymorphism profile that their PRLR harbors.

show abstract

Design and Synthesis of Protein Superfamily-Targeted Chemical Libraries for Lead Identification and Optimization

Cited by 24 publications

References 227 publications

Increased Diversity of Libraries from Libraries: Chemoinformatic Analysis of Bis‐Diazacyclic Libraries

Increased Diversity of Libraries from Libraries: Chemoinformatic Analysis of Bis‐Diazacyclic Libraries

High-Throughput Screening Assays to Discover Small-Molecule Inhibitors of Protein Interactions

Small Molecule Inhibitors of the Prolactin Receptor in Breast Cancer

Contact Info

Product

Resources

About