DESIGN OF NON-ATP COMPETITIVE INHIBITORS OF POLO-LIKE KINASES THROUGH "REPLACE"

Abstract

In this work the synthesis of peptide-small molecule hybrids have been accomplished aiming to evaluate their anti-tumor activity as inhibitors for the polo­ box domain of polo-like kinase 1 .

Polo-like kinases are mitotic kinases that regulate numerous cell cycle events, making them attractive targets for anti-cancer therapy. They contain the polo-box domain (PBD), which is a unique domain with a characteristic motif that opened up the possibility of designing of peptide-small molecules hybrids ligated using REPLACE strategy, by REplacement of part of the peptide (3 amino acids of the non-physiological peptide) with non-peptidic _ surrogates having free carboxylic group and molecular weight ranging 150- 300. Compounds that fulfilled the criteria were enumerated then docked using Ligandfit protocol, Acclerys Discovery Studio 2.1 software.

Those peptide-capping groups were synthesized using solid phase synthesis (Fmoc methodology) in an automated procedure. The synthesized structures that gave the right mass were purified using HPFC and HPLC methods.