O'Brien, Peter Andrew orcid.org/0000-0002-9966-1962, Gomez Angel, Andres, Klein, Hanna et al. (9 more authors) (Accepted: 2025) Modular Synthetic Platform for the Elaboration of Fragments in Three Dimensions for Fragment-Based Drug Discovery. Journal of the American Chemical Society. ISSN: 1520-5126 (In Press)
Abstract
Fragment-based drug discovery (FBDD) is a key strategy employed in the hit-to-lead phase of pharmaceutical development. The rate limiting step of this process is often identifying and optimising synthetic chemistry suitable for fragment elabora-tion, especially in 3-dimensions (3-D). To address this limitation, we herein present a modular platform for the systematic and programmable elaboration of 2-dimensional (2-D) fragment hits into lead-like 3-D compounds, utilising nine bifunction-al building blocks that explore a range of vectors in 3-D. The building blocks comprise: (i) rigid sp3-rich bicyclic cyclopro-pane-based structures to fix the vectors, and (ii) two synthetic handles – a protected cyclic amine and a cyclopropyl N-methyliminodiacetic acid (MIDA) boronate. To validate our approach, we present: (i) multi-gram scale synthesis of each 3-D building block; (ii) Suzuki-Miyaura cross-coupling reactions of the cyclopropyl BMIDA functionality with aryl bromides; (iii) N-functionalisation (via commonplace medicinal chemistry toolkit reactions) of arylated products to deliver 3-D lead-like compounds. Each building block accesses a distinct 3-D exit vector, as shown by analysis of the lowest energy confor-mations of lead-like molecules using RDKit, and by X-ray crystallography of pyrimidine methanesulfonamide derivatives. Since the synthetic methodology is established in advance of fragment screening and utilises robust chemistry, the elabora-tion of fragment hits in 3-D for biochemical screening can be achieved rapidly. To provide proof-of-concept, starting from the drug Ritlecitinib, the development of inhibitors of Janus kinase 3 (JAK3) around a putative pyrrolopyrimidine 2-D frag-ment hit was explored, streamlining the discovery of a novel and selective JAK3 inhibitor with IC50 = 69 nM.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This is an author-produced version of the published paper. Uploaded in accordance with the University’s Research Publications and Open Access policy. |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Funding Information: | Funder Grant number EPSRC EP/V048139/1 EPSRC EP/R51181X/1 THE ROYAL SOCIETY INF\R1\191028 |
Depositing User: | Pure (York) |
Date Deposited: | 30 Jul 2025 16:30 |
Last Modified: | 30 Jul 2025 16:30 |
Status: | In Press |
Refereed: | Yes |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:229799 |
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