Scaffold hopping from (5-hydroxymethyl) isophthalates to multisubstituted pyrimidines diminishes binding affinity to the C1 domain of protein kinase C

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Provenzani , R , Tarvainen , I M E , Brandoli , G , Lempinen , A T , Artes , S , Turku , A , Jäntti , M H , Talman , V , Yli-Kauhaluoma , J T , Tuominen , R K & Boije af Gennäs , P G 2018 , ' Scaffold hopping from (5-hydroxymethyl) isophthalates to multisubstituted pyrimidines diminishes binding affinity to the C1 domain of protein kinase C ' , PLoS One , vol. 13 , no. 4 , 0195668 . https://doi.org/10.1371/journal.pone.0195668

Title: Scaffold hopping from (5-hydroxymethyl) isophthalates to multisubstituted pyrimidines diminishes binding affinity to the C1 domain of protein kinase C
Author: Provenzani, Riccardo; Tarvainen, Ilari Matti Elias; Brandoli, Giulia; Lempinen, Antti Tapani; Artes, Sanna; Turku, Ainoleena; Jäntti, Maria Helena; Talman, Virpi; Yli-Kauhaluoma, Jari Tapani; Tuominen, Raimo Kalevi; Boije af Gennäs, Per Gustav
Contributor: University of Helsinki, Pharmaceutical Design and Discovery group
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Pharmaceutical Design and Discovery group
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Drug Research Program
University of Helsinki, Pharmaceutical Design and Discovery group
Date: 2018-04-11
Language: eng
Number of pages: 27
Belongs to series: PLoS One
ISSN: 1932-6203
URI: http://hdl.handle.net/10138/235212
Abstract: Protein kinase C (PKC) isoforms play a pivotal role in the regulation of numerous cellular functions, making them extensively studied and highly attractive drug targets. Utilizing the crystal structure of the PKC delta C1B domain, we have developed hydrophobic isophthalic acid derivatives that modify PKC functions by binding to the C1 domain of the enzyme. In the present study, we aimed to improve the drug-like properties of the isophthalic acid derivatives by increasing their solubility and enhancing the binding affinity. Here we describe the design and synthesis of a series of multisubstituted pyrimidines as analogs of C1 domain - targeted isophthalates and characterize their binding affinities to the PKC alpha isoform. In contrast to our computational predictions, the scaffold hopping from phenyl to pyrimidine core diminished the binding affinity. Although the novel pyrimidines did not establish improved binding affinity for PKC alpha compared to our previous isophthalic acid derivatives, the present results provide useful structure-activity relationship data for further development of ligands targeted to the C1 domain of PKC.
Subject: 116 Chemical sciences
317 Pharmacy
PHORBOL ESTER RECEPTO RS
BIOLOGICAL-ACTIVITY
DIACYLGLYCEROL DAG
CHEMICAL SPACE
PKC-ALPHA
DESIGN
SELECTIVITY
LIGAND
RASGRP
DERIVATIVES
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