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

DOI: 10.1039/D0SC01232G

Authors: Sarah L. Kidd (University of Cambridge) , Elaine Fowler (University of Cambridge) , Till Reinhardt (University of Cambridge) , Thomas Compton (University of Cambridge) , Natalia Mateu (University of Cambridge) , Hector Newman (University of Warwick; Diamond Light Source) , Dom Bellini (University of Warwick) , Romain Talon (Diamond Light Source; Structural Genomics Consortium (SGC), University of Oxford) , Joseph Mcloughlin (University of Cambridge) , Tobias Krojer (Target Discovery Institute, University of Oxford) , Anthony Aimon (Diamond Light Source; Structural Genomics Consortium (SGC), University of Oxford) , Anthony Bradley (Diamond Light Source) , Michael Fairhead (Structural Genomics Consortium (SGC), University of Oxford) , Paul Brear (University of Cambridge) , Laura Diaz-saez (Target Discovery Institute; Structural Genomics Consortium (SGC), University of Oxford) , Katherine Mcauley (Diamond Light Source) , Hannah F. Sore (University of Cambridge) , Andrew Madin (AstraZeneca) , Daniel H. O'donovan (AstraZeneca) , Kilian Huber (Target Discovery Institute; Structural Genomics Consortium (SGC), University of Oxford) , Marko Hyvonen (University of Cambridge) , Frank Von Delft (Diamond Light Source; Structural Genomics Consortium (SGC), University of Oxford; University of Johannesburg) , Christopher G. Dowson (University of Warwick) , David R. Spring (University of Cambridge)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Chemical Science

State: Published (Approved)
Published: May 2020
Diamond Proposal Number(s): 18145 , 15649 , 14303 , 14493

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.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Documents:
d0sc01232g.pdf