Optimization of non-ATP competitive CDK/cyclin groove inhibitors through REPLACE-mediated fragment assembly

Abstract

A major challenge in drug discovery is to develop and improve methods for targeting protein-protein interactions. Further exemplification of the REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) strategy for generating inhibitors of protein-protein interactions demonstrated that it can be used to optimize fragment alternatives of key determinants, to combine these in an effective way, and this was achieved for compounds targeting the cyclin-dependent kinase 2 (CDK2) substrate recruitment site on the cyclin regulatory subunit. Phenylheterocyclic isosteres replacing a critical charge-charge interaction provided new structural insights for binding to the cyclin groove. In particular, these results shed light onto the key contributions of a H-bond observed in crystal structures of N-terminally capped peptides. Furthermore, the structure-activity relationship of a bis(aryl) ether C-terminal capping group mimicking dipeptide interactions was probed through ring substitutions, allowing increased complementarity with the primary hydrophobic pocket. This study further validates REPLACE as an effective strategy for converting peptidic compounds to more pharmaceutically relevant compounds.

Figure 1

REPLACE mediated conversion of the octapeptide cyclin groove inhibitor HAKRRLIF into an N and C-terminally capped dipeptide. (Structures were modeled from PDB ID 2UUE).

Figure 2

Modeled structure of SCCP5773 in complex with CDK4/cyclin D1 (brown carbon atoms) overlayed with the crystal structure of the same Ncap bound to CDK2/cyclin A2 (yellow carbon atoms). A Connolly surface representation of cyclin A is shown along with the putative water molecule contributing bridging hydrogen bonds.

Scheme 1

Synthesis of phenyltriazole N-capping groups

Scheme 2

Synthesis of phenylpyrazole N-capping groups

Scheme 3

Synthesis of phenylfuran N-capping groups

Scheme 4

Synthesis of phenylpyrrole N-capping groups

Scheme 5

Synthesis of phenylimidazole N-capping groups