biostudies-literatureGomez-Angel ARRoyal SocietyEuropean CommissionUK Research and Innovation29292-29303https://www.ebi.ac.uk/biostudies/studies/S-EPMC12356528biostudies-literatureUnknown147(32)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 optimizing synthetic chemistry suitable for fragment elaboration, especially in three dimensions (3-D). To address this limitation, we herein present a modular platform for the systematic and programmable elaboration of two-dimensional (2-D) fragment hits into lead-like 3-D compounds, utilizing nine bifunctional building blocks that explore a range of vectors in 3-D. The building blocks comprise (i) rigid sp³-rich bicyclic cyclopropane-based structures to fix the vectors and (ii) two synthetic handles─a protected cyclic amine and a cyclopropyl <i>N-</i>methyliminodiacetic acid (MIDA) boronate. To vJournal of the American Chemical SocietyModular Synthetic Platform for the Elaboration of Fragments in Three Dimensions for Fragment-Based Drug Discovery.PMC12356528675899, FRAGNETINFR1191028EP/V048139/1Donald JRPalmer CJLincoln JLucas SCCAppiani RGomez-Angel ARYao SYFusani LKlein HFFirth JDO'Brien PStorer RIfalseModular Synthetic Platform for the Elaboration of Fragments in Three Dimensions for Fragment-Based Drug Discovery.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 optimizing synthetic chemistry suitable for fragment elaboration, especially in three dimensions (3-D). To address this limitation, we herein present a modular platform for the systematic and programmable elaboration of two-dimensional (2-D) fragment hits into lead-like 3-D compounds, utilizing nine bifunctional building blocks that explore a range of vectors in 3-D. The building blocks comprise (i) rigid sp³-rich bicyclic cyclopropane-based structures to fix the vectors and (ii) two synthetic handles─a protected cyclic amine and a cyclopropyl <i>N-</i>methyliminodiacetic acid (MIDA) boronate. To v2025-01-01T00:00:00Z2025 Aug2026-05-01T18:45:01.919Z2026-04-07T17:09:33.511ZS-EPMC123565284073744510.1021/jacs.5c08786