2. Academic Validation
  3. Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo

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

  • J Med Chem. 2022 Jun 23;65(12):8191-8207. doi: 10.1021/acs.jmedchem.1c02175.
Rosemary Huckvale 1,  Alice C Harnden 1,  Kwai-Ming J Cheung 1,  Olivier A Pierrat 1,  Rachel Talbot 1,  Gary M Box 1,  Alan T Henley 1,  Alexis K de Haven Brandon 1,  Albert E Hallsworth 1,  Michael D Bright 1,  Hafize Aysin Akpinar 1,  Daniel S J Miller 1,  Dalia Tarantino 1,  Sharon Gowan 1,  Angela Hayes 1,  Emma A Gunnell 1 2,  Alfie Brennan 1,  Owen A Davis 1,  Louise D Johnson 1,  Selby de Klerk 1,  Craig McAndrew 1,  Yann-Vaï Le Bihan 1 2,  Mirco Meniconi 1,  Rosemary Burke 1,  Vladimir Kirkin 1,  Rob L M van Montfort 1 2,  Florence I Raynaud 1,  Olivia W Rossanese 1,  Benjamin R Bellenie 1,  Swen Hoelder 1
Affiliations

Affiliations

  • 1 Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.
  • 2 Division of Structural Biology, The Institute of Cancer Research, London SM2 5NG, U.K.
PMID: 35653645 DOI: 10.1021/acs.jmedchem.1c02175
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 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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