Hot Topics in Medicinal Chemistry (Track)


Gerhard Müller

Senior Vice President Medicinal Chemistry, Mercachembv, PO Box 6747, 6503 GE Nijmegen, The Netherlands


In medicinal chemistry, drug discovery programs frequently struggle in achieving high cellular and in-vivo efficacy for a given compound series, despite excellent biochemical activities and good physicochemical properties of the frontrunner candidates. To improve the correlation between biochemical and the cellular and in vivo efficacy, it is advantageous to consider the lifetime of the ligand-target complex by optimizing the residence time (1/koff) of compound-target complexes.

This presentation highlights the relevance of binding kinetic attributes of kinase inhibitors, more specific the engineering of binding kinetic signatures exhibiting a slow koff into “deep-pocket-directed” scaffolds for achieving high efficacies in more complex biological test systems. We will demonstrate that a thorough understanding of the precise pharmacophoric requirements on the target’s binding site is essential to pre-engineer the desired slow off-rates into new scaffolds that qualify as privileged structures for the target family of kinases. The details of the so-called “retro-design” approach for type II kinase inhibitors will be exemplified by hit-to-lead and lead optimization campaigns that yielded novel and highly efficacious inhibitors for a variety of kinases [1].

Mercachem also applies novel design principles to next-generation HDAC (histone-deacetylases) inhibitors with predesigned slow off-rates by exploiting the conformational flexibility that is associated with the HDAC’s product release channel.

[1] G. Müller et al., IDrugs 2010, 13, 457-466.