학술논문
Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo
Document Type
Article
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
Source
Journal of Medicinal Chemistry; June 2022, Vol. 65 Issue: 12 p8191-8207, 17p
Subject
Language
ISSN
00222623; 15204804
Abstract
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 CCT369260to 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. CCT373566showed modest in vivoefficacy in a lymphoma xenograft mouse model following oral dosing.