Author: de Klerk, Selby ; Raynaud, Florence I. ; Hoelder, Swen ; Pierrat, Olivier A. ; Meniconi, Mirco ; Henley, Alan T. ; Burke, Rosemary ; Miller, Daniel S. J. ; van Montfort, Rob L. M. ; Valenti, Melanie ; Akpinar, Hafize Aysin ; Bright, Michael D. ; Harnden, Alice C. ; de Haven Brandon, Alexis K. ; Johnson, Louise D. ; Davis, Owen A. ; Le Bihan, Yann-Vai ; Bellenie, Benjamin R. ; McAndrew, Peter Craig ; Box, Gary M. ; Tarantino, Dalia ; Rossanese, Olivia W. ; Gowan, Sharon ; Huckvale, Rosemary ; Kirkin, Vladimir ; Hayes, Angela ; Talbot, Rachel ; Cheung, Kwai-Ming J. ; Brennan, Alfie

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.

23 Jun 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Hoelder, Swen ; de Klerk, Selby ; Miller, Daniel S. J. ; Henley, Alan T. ; Tarantino, Dalia ; Gowan, Sharon ; Gunnell, Emma A. ; Box, Gary M. ; Bellenie, Benjamin R. ; Hayes, Angela ; Rossanese, Olivia W. ; Pierrat, Olivier A. ; Harnden, Alice C. ; Meniconi, Mirco ; Le Bihan, Yann-Vaï ; Johnson, Louise D. ; Talbot, Rachel ; Hallsworth, Albert E. ; Cheung, Kwai-Ming J. ; Davis, Owen A. ; Burke, Rosemary ; Brennan, Alfie ; Huckvale, Rosemary ; McAndrew, Craig ; Bright, Michael D. ; van Montfort, Rob L. M. ; Kirkin, Vladimir ; Akpinar, Hafize Aysin ; Raynaud, Florence I. ; de Haven Brandon, Alexis K.

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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Indication	Highest Phase	Country/Location	Organization	Date
Lymphoma	Preclinical	GB	The Institute of Cancer Research: Royal Cancer Hospital	29 Mar 2022

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