title: Exploring the influence of indololactone structure on selectivity for binding to the C1 domains of PKCα, PKCε, and RasGRP.
abstract: C1 domain-containing proteins, such as protein kinase C (PKC), have a central role in cellular signal transduction. Their involvement in many diseases, including cancer, cardiovascular disease, and immunological and neurological disorders has been extensively demonstrated and has prompted a search for small molecules to modulate their activity. By employing a diacylglycerol (DAG)-lactone template, we have been able to develop ultra potent analogs of diacylglycerol with nanomolar binding affinities approaching those of complex natural products such as phorbol esters and bryostatins. One current challenge is the development of selective ligands capable of discriminating between different protein family members. Recently, structure-activity relationship studies have shown that the introduction of an indole ring as a DAG-lactone substituent yielded selective Ras guanine nucleotide-releasing protein (RasGRP1) activators when compared to PKCα and PKCε. In the present work, we examine the effects of ligand selectivity relative to the orientation of the indole ring and the nature of the DAG-lactone template itself. Our results show that the indole ring must be attached to the lactone moiety through the sn-2 position in order to achieve RasGRP1 selectivity.
authors.affiliation: Laboratory of Organic Synthesis, Center of Research and Development in Chemistry, National Institute of Industrial Technology, Buenos Aires, Argentina.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Elhalem
authors.affiliation: Laboratory of Organic Synthesis, Center of Research and Development in Chemistry, National Institute of Industrial Technology, Buenos Aires, Argentina.
authors.forename: Lucía Gandolfi
authors.initials: LG
authors.lastname: Donadío
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lewin
authors.affiliation: Laboratory of Organic Synthesis, Center of Research and Development in Chemistry, National Institute of Industrial Technology, Buenos Aires, Argentina.
authors.forename: Lia C
authors.initials: LC
authors.lastname: Garcia
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Lai
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Kelley
authors.affiliation: Basic Science Program, Leidos Biomedical Research Inc., Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Peach
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.affiliation: Laboratory of Organic Synthesis, Center of Research and Development in Chemistry, National Institute of Industrial Technology, Buenos Aires, Argentina. Electronic address: jcomin@inti.gob.ar.
authors.forename: María J
authors.initials: MJ
authors.lastname: Comin
mesh_terms: D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011485:Protein Binding; D000072417:Protein Domains; D051571:Protein Kinase C-alpha / Q000737:chemistry / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D007211:Indoles; D007783:Lactones; C491790:RASGRP1 protein, human; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon