Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo.
Date
2022-06-23ICR Author
Author
Huckvale, R
Harnden, AC
Cheung, K-MJ
Pierrat, OA
Talbot, R
Box, GM
Henley, AT
de Haven Brandon, AK
Hallsworth, AE
Bright, MD
Akpinar, HA
Miller, DSJ
Tarantino, D
Gowan, S
Hayes, A
Gunnell, EA
Brennan, A
Davis, OA
Johnson, LD
de Klerk, S
McAndrew, C
Le Bihan, Y-V
Meniconi, M
Burke, R
Kirkin, V
van Montfort, RLM
Raynaud, FI
Rossanese, OW
Bellenie, BR
Hoelder, S
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Animals
Carcinogenesis
Gene Expression Regulation, Neoplastic
Humans
Mice
Proto-Oncogene Proteins c-bcl-6
Research team
Hit Discov Struct Design
Clinical Pharma & Trials
Directorate Canc Ther
Medicinal Chemistry 4
Language
eng
Date accepted
2022-06-03
License start date
2022-06-23
Citation
Journal of Medicinal Chemistry, 2022, 65 (12), pp. 8191 - 8207
Publisher
AMER CHEMICAL SOC