
Issue 39, 2020

Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion

Abstract

Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Firstly, we demonstrate the importance for diversity in aiding hit identification with four fragment binders resulting from these efforts. Moreover, we also exemplify the ability to readily access a library of analogues from cheap commercially available materials, which ultimately enabled the exploration of a minimum of four synthetic vectors from each molecule. In total, 10–14 analogues of each hit were rapidly accessed in three to six synthetic steps. Thus, we showcase how DOS-derived fragment libraries enable efficient hit derivatisation and can be utilised to remove the synthetic limitations encountered in early stage fragment-based drug discovery.

Supplementary files

Article information

Article type
Edge Article
Submitted
28 Feb 2020
Accepted
14 May 2020
First published
14 May 2020
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 10792-10801

Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion

S. L. Kidd, E. Fowler, T. Reinhardt, T. Compton, N. Mateu, H. Newman, D. Bellini, R. Talon, J. McLoughlin, T. Krojer, A. Aimon, A. Bradley, M. Fairhead, P. Brear, L. Díaz-Sáez, K. McAuley, H. F. Sore, A. Madin, D. H. O'Donovan, K. V. M. Huber, M. Hyvönen, F. von Delft, C. G. Dowson and D. R. Spring, Chem. Sci., 2020, 11, 10792 DOI: 10.1039/D0SC01232G

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.

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