Correction: Identification of the key structural elements of a dihydropyrimidinone core driving toward more potent Hsp90 C-terminal inhibitors

Correction for 'Identification of the key structural elements of a dihydropyrimidinone core driving toward more potent Hsp90 C-terminal inhibitors' by S. Teracciano et al., Chem. Commun., 2016, 52, 12857–12860

Targeting the Hsp90 C-terminal domain by the chemically accessible dihydropyrimidinone scaffold

Hsp90 C-terminal ligands are potential new anti-cancer drugs alternative to the more studied N-terminal inhibitors. Here we report the identification of a new dihydropyrimidinone binding the C-terminus, which is not structurally related to other well-known natural and natureinspired inhibitors of this second druggable Hsp90 site

3,4-dihydropyrimidin-2(1H)-one as a useful scaffold for Hsp90 C-terminal inhibition

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that plays a crucial role in stabilizing and activating more than 200 “client proteins”, many of which are involved in signal transduction, cell cycle regulation and apoptosis [1]. Therefore a considerable interest in developing chemotherapeutic drugs that specifically disrupt the function of Hsp90 has aroused. Recently several N-terminal Hsp90 inhibitors have been identified and are currently in clinical trials, while only few C-terminal inhibitors have been reported. Here we describe the synthesis of 3,4- dihydropyrimidin-2(1H)-ones performed through a microwave-assisted Biginelli reaction [2]. These compounds have been extensively evaluated for their biological activity using several assays including surface plasmon resonance (SPR), inhibition of cell proliferation and cell cycle arrest, depletion of client proteins. From these studies a new promising molecule has emerged. In order to identify the binding site on the target protein we have performed limited proteolysis experiments which suggested the interaction of the compound with the C-terminal domain of Hsp90 and a binding mode has been proposed by molecular docking

Identification of the key structural elements of a dihydropyrimidinone core driving toward more potent Hsp90 C-terminal inhibitors

Hsp90 C-terminal modulation represents an attractive strategy for the development of potent and safer antitumor compounds. Continuing our investigation on DHPM type inhibitors here we report a new set of potent C-terminal ligands which allowed us to identify the key structural features crucial for the biological activity