NOVEL KINASE INHIBITORS WITH PRE-ENGINEERED SLOW OFF-RATES
Senior Vice President Medicinal Chemistry, Mercachembv, PO Box 6747, 6503 GE Nijmegen, The
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 .
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