Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP
- Autores
- Garcia, Lia C.; Gandolfi Donadío, Lucía; Mann, Ella; Kolusheva, Sofiya; Kedei, Noemi; Lewin, Nancy E.; Hill, Collin S.; Kelsey, Jessica S.; Yang, Jing; Esch, Timothy E.; Santos, Marina; Peach, Megan L.; Kelley, James A.; Blumberg, Peter M.; Jelinek, Raz; Marquez, Victor E.; Comin, Maria Julieta
- Año de publicación
- 2014
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2–5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined.
Fil: Garcia, Lia C.. Instituto Nacional de Tecnología Industrial; Argentina
Fil: Gandolfi Donadío, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina
Fil: Mann, Ella. Ben Gurion University of The Negev; Israel
Fil: Kolusheva, Sofiya. Ben Gurion University of The Negev; Israel
Fil: Kedei, Noemi. National Cancer Institute. Bethesda; Estados Unidos
Fil: Lewin, Nancy E.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Hill, Collin S.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Kelsey, Jessica S.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Yang, Jing. National Cancer Institute. Bethesda; Estados Unidos
Fil: Esch, Timothy E.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Santos, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina
Fil: Peach, Megan L.. National Institutes of Health; Estados Unidos
Fil: Kelley, James A.. National Institutes of Health; Estados Unidos
Fil: Blumberg, Peter M.. National Cancer Institute. Bethesda; Estados Unidos
Fil: Jelinek, Raz. Ben Gurion University of The Negev; Israel
Fil: Marquez, Victor E.. National Institutes of Health; Estados Unidos
Fil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina - Materia
-
Indolo-Lactones
C1 Domain
Rasgrp
Cancer - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/35694
Ver los metadatos del registro completo
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Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRPGarcia, Lia C.Gandolfi Donadío, LucíaMann, EllaKolusheva, SofiyaKedei, NoemiLewin, Nancy E.Hill, Collin S.Kelsey, Jessica S.Yang, JingEsch, Timothy E.Santos, MarinaPeach, Megan L.Kelley, James A.Blumberg, Peter M.Jelinek, RazMarquez, Victor E.Comin, Maria JulietaIndolo-LactonesC1 DomainRasgrpCancerhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2–5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined.Fil: Garcia, Lia C.. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Gandolfi Donadío, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Mann, Ella. Ben Gurion University of The Negev; IsraelFil: Kolusheva, Sofiya. Ben Gurion University of The Negev; IsraelFil: Kedei, Noemi. National Cancer Institute. Bethesda; Estados UnidosFil: Lewin, Nancy E.. National Cancer Institute. Bethesda; Estados UnidosFil: Hill, Collin S.. National Cancer Institute. Bethesda; Estados UnidosFil: Kelsey, Jessica S.. National Cancer Institute. Bethesda; Estados UnidosFil: Yang, Jing. National Cancer Institute. Bethesda; Estados UnidosFil: Esch, Timothy E.. National Cancer Institute. Bethesda; Estados UnidosFil: Santos, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Peach, Megan L.. National Institutes of Health; Estados UnidosFil: Kelley, James A.. National Institutes of Health; Estados UnidosFil: Blumberg, Peter M.. National Cancer Institute. Bethesda; Estados UnidosFil: Jelinek, Raz. Ben Gurion University of The Negev; IsraelFil: Marquez, Victor E.. National Institutes of Health; Estados UnidosFil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; ArgentinaPergamon-Elsevier Science Ltd.2014-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/35694Garcia, Lia C.; Gandolfi Donadío, Lucía; Mann, Ella; Kolusheva, Sofiya; Kedei, Noemi; et al.; Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP; Pergamon-Elsevier Science Ltd.; Bioorganic & Medicinal Chemistry; 22; 12; 6-2014; 3123-31400968-0896CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.bmc.2014.04.024info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0968089614002788info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:48:54Zoai:ri.conicet.gov.ar:11336/35694instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:48:54.595CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP |
title |
Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP |
spellingShingle |
Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP Garcia, Lia C. Indolo-Lactones C1 Domain Rasgrp Cancer |
title_short |
Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP |
title_full |
Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP |
title_fullStr |
Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP |
title_full_unstemmed |
Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP |
title_sort |
Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP |
dc.creator.none.fl_str_mv |
Garcia, Lia C. Gandolfi Donadío, Lucía Mann, Ella Kolusheva, Sofiya Kedei, Noemi Lewin, Nancy E. Hill, Collin S. Kelsey, Jessica S. Yang, Jing Esch, Timothy E. Santos, Marina Peach, Megan L. Kelley, James A. Blumberg, Peter M. Jelinek, Raz Marquez, Victor E. Comin, Maria Julieta |
author |
Garcia, Lia C. |
author_facet |
Garcia, Lia C. Gandolfi Donadío, Lucía Mann, Ella Kolusheva, Sofiya Kedei, Noemi Lewin, Nancy E. Hill, Collin S. Kelsey, Jessica S. Yang, Jing Esch, Timothy E. Santos, Marina Peach, Megan L. Kelley, James A. Blumberg, Peter M. Jelinek, Raz Marquez, Victor E. Comin, Maria Julieta |
author_role |
author |
author2 |
Gandolfi Donadío, Lucía Mann, Ella Kolusheva, Sofiya Kedei, Noemi Lewin, Nancy E. Hill, Collin S. Kelsey, Jessica S. Yang, Jing Esch, Timothy E. Santos, Marina Peach, Megan L. Kelley, James A. Blumberg, Peter M. Jelinek, Raz Marquez, Victor E. Comin, Maria Julieta |
author2_role |
author author author author author author author author author author author author author author author author |
dc.subject.none.fl_str_mv |
Indolo-Lactones C1 Domain Rasgrp Cancer |
topic |
Indolo-Lactones C1 Domain Rasgrp Cancer |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.4 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2–5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined. Fil: Garcia, Lia C.. Instituto Nacional de Tecnología Industrial; Argentina Fil: Gandolfi Donadío, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina Fil: Mann, Ella. Ben Gurion University of The Negev; Israel Fil: Kolusheva, Sofiya. Ben Gurion University of The Negev; Israel Fil: Kedei, Noemi. National Cancer Institute. Bethesda; Estados Unidos Fil: Lewin, Nancy E.. National Cancer Institute. Bethesda; Estados Unidos Fil: Hill, Collin S.. National Cancer Institute. Bethesda; Estados Unidos Fil: Kelsey, Jessica S.. National Cancer Institute. Bethesda; Estados Unidos Fil: Yang, Jing. National Cancer Institute. Bethesda; Estados Unidos Fil: Esch, Timothy E.. National Cancer Institute. Bethesda; Estados Unidos Fil: Santos, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina Fil: Peach, Megan L.. National Institutes of Health; Estados Unidos Fil: Kelley, James A.. National Institutes of Health; Estados Unidos Fil: Blumberg, Peter M.. National Cancer Institute. Bethesda; Estados Unidos Fil: Jelinek, Raz. Ben Gurion University of The Negev; Israel Fil: Marquez, Victor E.. National Institutes of Health; Estados Unidos Fil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina |
description |
The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2–5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined. |
publishDate |
2014 |
dc.date.none.fl_str_mv |
2014-06 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/35694 Garcia, Lia C.; Gandolfi Donadío, Lucía; Mann, Ella; Kolusheva, Sofiya; Kedei, Noemi; et al.; Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP; Pergamon-Elsevier Science Ltd.; Bioorganic & Medicinal Chemistry; 22; 12; 6-2014; 3123-3140 0968-0896 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/35694 |
identifier_str_mv |
Garcia, Lia C.; Gandolfi Donadío, Lucía; Mann, Ella; Kolusheva, Sofiya; Kedei, Noemi; et al.; Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP; Pergamon-Elsevier Science Ltd.; Bioorganic & Medicinal Chemistry; 22; 12; 6-2014; 3123-3140 0968-0896 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bmc.2014.04.024 info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0968089614002788 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Pergamon-Elsevier Science Ltd. |
publisher.none.fl_str_mv |
Pergamon-Elsevier Science Ltd. |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1842268944944070656 |
score |
13.13397 |