8 research outputs found
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