Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo

[Image: see text] The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 to CCT373566, a highly potent probe suitable for sustaine...

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Autores principales: Huckvale, Rosemary, Harnden, Alice C., Cheung, Kwai-Ming J., Pierrat, Olivier A., Talbot, Rachel, Box, Gary M., Henley, Alan T., de Haven Brandon, Alexis K., Hallsworth, Albert E., Bright, Michael D., Akpinar, Hafize Aysin, Miller, Daniel S. J., Tarantino, Dalia, Gowan, Sharon, Hayes, Angela, Gunnell, Emma A., Brennan, Alfie, Davis, Owen A., Johnson, Louise D., de Klerk, Selby, McAndrew, 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 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234961/
https://www.ncbi.nlm.nih.gov/pubmed/35653645
http://dx.doi.org/10.1021/acs.jmedchem.1c02175
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author Huckvale, Rosemary
Harnden, Alice C.
Cheung, Kwai-Ming J.
Pierrat, Olivier A.
Talbot, Rachel
Box, Gary M.
Henley, Alan T.
de Haven Brandon, Alexis K.
Hallsworth, Albert E.
Bright, Michael D.
Akpinar, Hafize Aysin
Miller, Daniel S. J.
Tarantino, Dalia
Gowan, Sharon
Hayes, Angela
Gunnell, Emma A.
Brennan, Alfie
Davis, Owen A.
Johnson, Louise D.
de Klerk, Selby
McAndrew, 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 Huckvale, Rosemary
Harnden, Alice C.
Cheung, Kwai-Ming J.
Pierrat, Olivier A.
Talbot, Rachel
Box, Gary M.
Henley, Alan T.
de Haven Brandon, Alexis K.
Hallsworth, Albert E.
Bright, Michael D.
Akpinar, Hafize Aysin
Miller, Daniel S. J.
Tarantino, Dalia
Gowan, Sharon
Hayes, Angela
Gunnell, Emma A.
Brennan, Alfie
Davis, Owen A.
Johnson, Louise D.
de Klerk, Selby
McAndrew, 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 Huckvale, Rosemary
collection PubMed
description [Image: see text] The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 to CCT373566, a highly potent probe suitable for sustained depletion of BCL6 in vivo. We observed a sharp degradation SAR, where subtle structural changes conveyed the ability to induce degradation of BCL6. CCT373566 showed modest in vivo efficacy in a lymphoma xenograft mouse model following oral dosing.
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spelling pubmed-92349612022-06-28 Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo Huckvale, Rosemary Harnden, Alice C. Cheung, Kwai-Ming J. Pierrat, Olivier A. Talbot, Rachel Box, Gary M. Henley, Alan T. de Haven Brandon, Alexis K. Hallsworth, Albert E. Bright, Michael D. Akpinar, Hafize Aysin Miller, Daniel S. J. Tarantino, Dalia Gowan, Sharon Hayes, Angela Gunnell, Emma A. Brennan, Alfie Davis, Owen A. Johnson, Louise D. de Klerk, Selby McAndrew, 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] The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 to CCT373566, a highly potent probe suitable for sustained depletion of BCL6 in vivo. We observed a sharp degradation SAR, where subtle structural changes conveyed the ability to induce degradation of BCL6. CCT373566 showed modest in vivo efficacy in a lymphoma xenograft mouse model following oral dosing. American Chemical Society 2022-06-02 2022-06-23 /pmc/articles/PMC9234961/ /pubmed/35653645 http://dx.doi.org/10.1021/acs.jmedchem.1c02175 Text en © 2022 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 Huckvale, Rosemary
Harnden, Alice C.
Cheung, Kwai-Ming J.
Pierrat, Olivier A.
Talbot, Rachel
Box, Gary M.
Henley, Alan T.
de Haven Brandon, Alexis K.
Hallsworth, Albert E.
Bright, Michael D.
Akpinar, Hafize Aysin
Miller, Daniel S. J.
Tarantino, Dalia
Gowan, Sharon
Hayes, Angela
Gunnell, Emma A.
Brennan, Alfie
Davis, Owen A.
Johnson, Louise D.
de Klerk, Selby
McAndrew, 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
Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo
title Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo
title_full Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo
title_fullStr Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo
title_full_unstemmed Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo
title_short Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo
title_sort improved binding affinity and pharmacokinetics enable sustained degradation of bcl6 in vivo
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234961/
https://www.ncbi.nlm.nih.gov/pubmed/35653645
http://dx.doi.org/10.1021/acs.jmedchem.1c02175
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