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

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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.
Originalspråkengelska
Artikelnummer e0195668
TidskriftPLoS One
Volym13
Utgåva4
Antal sidor27
ISSN1932-6203
DOI
StatusPublicerad - 11 apr 2018
MoE-publikationstypA1 Tidskriftsartikel-refererad

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@article{e90df260731841f9a4d98b680453672b,
title = "Scaffold hopping from (5-hydroxymethyl) isophthalates to multisubstituted pyrimidines diminishes binding affinity to the C1 domain of protein kinase C",
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.",
keywords = "116 Chemical sciences, 317 Pharmacy, PHORBOL ESTER RECEPTO RS, BIOLOGICAL-ACTIVITY, DIACYLGLYCEROL DAG, CHEMICAL SPACE, PKC-ALPHA, DESIGN, SELECTIVITY, LIGAND, RASGRP, DERIVATIVES",
author = "Riccardo Provenzani and Tarvainen, {Ilari Matti Elias} and Giulia Brandoli and Lempinen, {Antti Tapani} and Sanna Artes and Ainoleena Turku and J{\"a}ntti, {Maria Helena} and Virpi Talman and Yli-Kauhaluoma, {Jari Tapani} and Tuominen, {Raimo Kalevi} and {Boije af Genn{\"a}s}, {Per Gustav}",
year = "2018",
month = "4",
day = "11",
doi = "10.1371/journal.pone.0195668",
language = "English",
volume = "13",
journal = "PLoS One",
issn = "1932-6203",
publisher = "PUBLIC LIBRARY OF SCIENCE",
number = "4",

}

TY - JOUR

T1 - Scaffold hopping from (5-hydroxymethyl) isophthalates to multisubstituted pyrimidines diminishes binding affinity to the C1 domain of protein kinase C

AU - Provenzani, Riccardo

AU - Tarvainen, Ilari Matti Elias

AU - Brandoli, Giulia

AU - Lempinen, Antti Tapani

AU - Artes, Sanna

AU - Turku, Ainoleena

AU - Jäntti, Maria Helena

AU - Talman, Virpi

AU - Yli-Kauhaluoma, Jari Tapani

AU - Tuominen, Raimo Kalevi

AU - Boije af Gennäs, Per Gustav

PY - 2018/4/11

Y1 - 2018/4/11

N2 - 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.

AB - 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.

KW - 116 Chemical sciences

KW - 317 Pharmacy

KW - PHORBOL ESTER RECEPTO RS

KW - BIOLOGICAL-ACTIVITY

KW - DIACYLGLYCEROL DAG

KW - CHEMICAL SPACE

KW - PKC-ALPHA

KW - DESIGN

KW - SELECTIVITY

KW - LIGAND

KW - RASGRP

KW - DERIVATIVES

U2 - 10.1371/journal.pone.0195668

DO - 10.1371/journal.pone.0195668

M3 - Article

VL - 13

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e0195668

ER -