Kinetic Target-Guided Synthesis: Reaching the Age of Maturity

Damien Bosc (1) , Virgyl Camberlein (1) , Ronan Gealageas (1) , Omar Castillo-Aguilera (1) , Benoit Deprez (1) , Rébecca F. Déprez-Poulain (1, 2)

1 M2SV - Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177
2 IUF - Institut universitaire de France

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.

Mots clés: KTGS; triazole; fragment; in situ click chemistry; hit-to-lead; lead-optimization

Domaines: Sciences pharmaceutiques

Damien Bosc, Virgyl Camberlein, Ronan Gealageas, Omar Castillo-Aguilera, Benoit Deprez, et al.. Kinetic Target-Guided Synthesis: Reaching the Age of Maturity. Journal of Medicinal Chemistry, 2019, 63 (8), pp.3817-3833. ⟨10.1021/acs.jmedchem.9b01183⟩. ⟨hal-03051818⟩