C1 domain-targeted isophthalates as protein kinase C modulators: structure-based design, structure–activity relationships and biological activities

Abstract

Protein kinase C (PKC) is a serine/threonine kinase belonging to the AGC family. PKC isoenzymes are activated by phospholipid-derived second messengers, transmit their signal by phosphorylating specific substrates and play a pivotal role in the regulation of various cell functions, including metabolism, growth, differentiation and apoptosis. Therefore they represent an interesting molecular target for the treatment of several diseases, such as cancer and Alzheimer's disease. Adopting a structure-based approach on the crystal structure of the PKCδ C1B domain, our team has developed isophthalic acid derivatives that are able to modify PKC functions by binding to the C1 domain of the enzyme. Bis[3-(trifluoromethyl)benzyl] 5-(hydroxymethyl)isophthalate (HMI-1a3) and bis(1-ethylpentyl) 5-(hydroxymethyl)isophthalate (HMI-1b11) were selected from a set of compounds for further studies due to their high affinity for the C1 domains of PKCα and PKCδ. HMI-1a3 showed marked antiproliferative activity in HeLa cells whereas HMI-1b11 induced differentiation and supported neurite growth in SH-SY5Y cells. Our aim in the future is to improve the selectivity and potency of isophthalate derivatives, to clarify their mechanism of action in the cellular environment and to assess their efficacy in cell-based and in vivo disease models. HMI-1a3 has already been selected for a further project and redesigned to function as a probe immobilized on an affinity chromatography column. It will be used to identify cellular target proteins from cell lysates, providing new insights into the mechanism of action of HMI-1a3.

Electroacupuncture Alleviates Diabetic Neuropathic Pain and Downregulates p‐PKC and TRPV1 in Dorsal Root Ganglions and Spinal Cord Dorsal Horn

“…PKC is a phospholipid-dependent serine/ threonine kinase family. Tis family comprises 13 isoenzymes that can be activated by extracellular signals [40]. Te active state of PKC is p-PKC, which is a phosphorylated state [41,42] and is implicated in various roles [43].…”

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

“…Plant and animal derived natural C1 domain ligands, such as phorbol esters and bryostatins, show high affinity and biological activity but they are not optimal drug candidates as their complex chemical structures make their synthesis tedious. In our previous work, we have demonstrated that simple 5-hydroxymethyl isophthalic acid derivatives exhibit promising biological activity [ 9 , 10 , 12 , 13 ]. The lipophilicity values for the HMIs (clog P 6–7) are however higher than the Lipinski’s drug-like lipophilic property value (log P ≤5) [ 27 ] and therefore, we endeavored to synthesize a new set of compounds with reduced lipophilicity and retained/increased binding affinity.…”

“…Moreover, as the ATP binding site in the catalytic domain is highly preserved throughout the human kinome, targeting the regulatory C1 domain greatly increases the selectivity for PKC over other kinases [ 6 , 7 ]. In addition to PKCs, there are only six other protein families, compared to more than 500 protein kinases in the human genome, containing a DAG-responsive C1 domain [ 8 – 10 ]. Throughout the years, several PKC activators showing higher affinity than the natural DAG were described and they represent a significant class of PKC modulators [ 11 ].…”

Protein Kinase C Activation as a Potential Therapeutic Strategy in Alzheimer's Disease: Is there a Role for Embryonic Lethal Abnormal Vision‐like Proteins?

“…Although various synthetic bryostatin analogues have been reported , to our knowledge, there are no reports of their effects in AD models. Among other C1 domain‐targeted compounds, the isophthalate derivatives act as partial agonists for PKC . They bind to PKC at submicromolar concentrations and activate PKC in cellular context as shown by induction of PKC‐dependent ERK1/2 phosphorylation .…”