Kinetic Target-Guided Synthesis: Reaching the Age of Maturity

Abstract

Kinetic target-guided synthesis (KTGS) is an original discovery strategy allowing a target to catalyze the irreversible synthesis of its own ligands from a pool of reagents. Though pioneered almost two decades ago, it only recently proved its usefulness in medicinal chemistry, as exemplified by the increasing number of protein targets used, the wider range of target and pocket types, and the diversity of therapeutic areas explored. In recent years, two new leads for in vivo studies were released. Amidations and multicomponent reactions expanded the armamentarium of reactions beyond triazole formation and two new examples of in cellulo KTGS were also disclosed. Herein, we analyze the origins and the chemical space of both KTGS ligands and warhead-bearing reagents. We review the KTGS timeline focusing on recent cases in order to give medicinal chemists the full scope of this strategy which has great potential for hit discovery and hit or lead optimization.

Design, synthesis, and evaluation of peptide‐imidazo[1,2‐a]pyrazine bioconjugates as potential bivalent inhibitors of the VirB11 ATPase HP0525

“…One possible explanation for this is that the linker between the 8‐amino imidazo[1,2‐ a ]pyrazine and the peptide fragment has the wrong length and/or structure to correctly orient the peptide fragment for binding to the next subunit. Whereas further detailed docking studies might help to identify improved linkers, a more powerful approach would undoubtably be to use a peptide aptamer “Trojan Horse” 57 or an enzyme‐templated fragment elaboration strategy, 58,59 in which the enzyme itself selects the correct combination of linker and peptide fragment for effective bivalent binding from a small library. A second explanation is that the β9‐αF‐β10 segment of HP0525, and smaller fragments, do not fold in such a way as to form effective mimics of the HP0525 subunit interface, or that this segment cannot compete with the complete protein during assembly of the hexamer.…”

Molecular Design in Practice: A Review of Selected Projects in a French Research Institute That Illustrates the Link between Chemical Biology and Medicinal Chemistry

“…Dynamic combinatorial chemistry (DCC) [ 24 ] and kinetic target-guided synthesis (KTGS) use the targeted protein as a template to create its own ligands from biocompatible and reactive reagents. In KTGS, the irreversible reaction between the reagents occurs following their binding to the targeted protein that brings them in close proximity and properly orients their compatible reactive moieties ( Figure 4 A) [ 25 , 26 , 27 ]. Azides and alkynes are the biocompatible reagents, which are the most employed and produce protein-templated triazoles by in situ click chemistry, a class of KTGS.…”

“Clicking“ fragment leads to novel dual-binding cholinesterase inhibitors

“…TGS includes methods based on reversible reactions (dynamic combinatorial libraries), in which the presence of an enzyme shifts the equilibrium between interchanging products with preference to the best binders 10 , and methods using enzyme-catalyzed irreversible reactions where the products with the highest affinity to the enzyme are produced exclusively 11 . Both methods provide an effective tool for screening of large numbers of potential ligands.…”