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Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones

[Image: see text] B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and...

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Autores principales: Harnden, Alice C., Davis, Owen A., Box, Gary M., Hayes, Angela, Johnson, Louise D., Henley, Alan T., de Haven Brandon, Alexis K., Valenti, Melanie, Cheung, Kwai-Ming J., Brennan, Alfie, Huckvale, Rosemary, Pierrat, Olivier A., Talbot, Rachel, Bright, Michael D., Akpinar, Hafize Aysin, Miller, Daniel S. J., Tarantino, Dalia, Gowan, Sharon, de Klerk, Selby, McAndrew, Peter Craig, Le Bihan, Yann-Vaï, Meniconi, Mirco, Burke, Rosemary, Kirkin, Vladimir, van Montfort, Rob L. M., Raynaud, Florence I., Rossanese, Olivia W., Bellenie, Benjamin R., Hoelder, Swen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150366/
https://www.ncbi.nlm.nih.gov/pubmed/37026591
http://dx.doi.org/10.1021/acs.jmedchem.3c00155
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author Harnden, Alice C.
Davis, Owen A.
Box, Gary M.
Hayes, Angela
Johnson, Louise D.
Henley, Alan T.
de Haven Brandon, Alexis K.
Valenti, Melanie
Cheung, Kwai-Ming J.
Brennan, Alfie
Huckvale, Rosemary
Pierrat, Olivier A.
Talbot, Rachel
Bright, Michael D.
Akpinar, Hafize Aysin
Miller, Daniel S. J.
Tarantino, Dalia
Gowan, Sharon
de Klerk, Selby
McAndrew, Peter Craig
Le Bihan, Yann-Vaï
Meniconi, Mirco
Burke, Rosemary
Kirkin, Vladimir
van Montfort, Rob L. M.
Raynaud, Florence I.
Rossanese, Olivia W.
Bellenie, Benjamin R.
Hoelder, Swen
author_facet Harnden, Alice C.
Davis, Owen A.
Box, Gary M.
Hayes, Angela
Johnson, Louise D.
Henley, Alan T.
de Haven Brandon, Alexis K.
Valenti, Melanie
Cheung, Kwai-Ming J.
Brennan, Alfie
Huckvale, Rosemary
Pierrat, Olivier A.
Talbot, Rachel
Bright, Michael D.
Akpinar, Hafize Aysin
Miller, Daniel S. J.
Tarantino, Dalia
Gowan, Sharon
de Klerk, Selby
McAndrew, Peter Craig
Le Bihan, Yann-Vaï
Meniconi, Mirco
Burke, Rosemary
Kirkin, Vladimir
van Montfort, Rob L. M.
Raynaud, Florence I.
Rossanese, Olivia W.
Bellenie, Benjamin R.
Hoelder, Swen
author_sort Harnden, Alice C.
collection PubMed
description [Image: see text] B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and in vivo exposure of the non-degrading isomer, CCT373567, of our recently published degrader, CCT373566. The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of CCT374705, a potent inhibitor of BCL6 with a good in vivo profile. Modest in vivo efficacy was achieved in a lymphoma xenograft mouse model after oral dosing.
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spelling pubmed-101503662023-05-02 Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones Harnden, Alice C. Davis, Owen A. Box, Gary M. Hayes, Angela Johnson, Louise D. Henley, Alan T. de Haven Brandon, Alexis K. Valenti, Melanie Cheung, Kwai-Ming J. Brennan, Alfie Huckvale, Rosemary Pierrat, Olivier A. Talbot, Rachel Bright, Michael D. Akpinar, Hafize Aysin Miller, Daniel S. J. Tarantino, Dalia Gowan, Sharon de Klerk, Selby McAndrew, Peter Craig Le Bihan, Yann-Vaï Meniconi, Mirco Burke, Rosemary Kirkin, Vladimir van Montfort, Rob L. M. Raynaud, Florence I. Rossanese, Olivia W. Bellenie, Benjamin R. Hoelder, Swen J Med Chem [Image: see text] B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and in vivo exposure of the non-degrading isomer, CCT373567, of our recently published degrader, CCT373566. The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of CCT374705, a potent inhibitor of BCL6 with a good in vivo profile. Modest in vivo efficacy was achieved in a lymphoma xenograft mouse model after oral dosing. American Chemical Society 2023-04-07 /pmc/articles/PMC10150366/ /pubmed/37026591 http://dx.doi.org/10.1021/acs.jmedchem.3c00155 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Harnden, Alice C.
Davis, Owen A.
Box, Gary M.
Hayes, Angela
Johnson, Louise D.
Henley, Alan T.
de Haven Brandon, Alexis K.
Valenti, Melanie
Cheung, Kwai-Ming J.
Brennan, Alfie
Huckvale, Rosemary
Pierrat, Olivier A.
Talbot, Rachel
Bright, Michael D.
Akpinar, Hafize Aysin
Miller, Daniel S. J.
Tarantino, Dalia
Gowan, Sharon
de Klerk, Selby
McAndrew, Peter Craig
Le Bihan, Yann-Vaï
Meniconi, Mirco
Burke, Rosemary
Kirkin, Vladimir
van Montfort, Rob L. M.
Raynaud, Florence I.
Rossanese, Olivia W.
Bellenie, Benjamin R.
Hoelder, Swen
Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones
title Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones
title_full Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones
title_fullStr Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones
title_full_unstemmed Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones
title_short Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones
title_sort discovery of an in vivo chemical probe for bcl6 inhibition by optimization of tricyclic quinolinones
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150366/
https://www.ncbi.nlm.nih.gov/pubmed/37026591
http://dx.doi.org/10.1021/acs.jmedchem.3c00155
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