Improved binding affinity and pharmacokinetics enables sustained degradation of BCL6 in vivo

Background: The transcriptional repressor BCL6 is an oncogenic driver often found to be deregulated in lymphoid malignancies. We report the optimisation of our previously reported benzimidazolone molecular glue type degrader CCT369260 CCT373566, a highly potent probe suitable for sustained depletion vivo. Materials and methods: Key discovering CCT373566 were two design approaches: 1) careful, property focused piperidine moiety reduce lipophilicity whilst maintaining ability degrade cells, 2) replacing with tricyclic quinolinone core that showed significantly tighter binding BTB domain. In vitro vivo profiling will demonstrated, including application xenograft models lymphoma. Results: During this optimisation, we observed sharp degradation SAR, where subtle structural changes conveyed induce BCL6. Our resulting lead has improved pharmacokinetics activity compared CCT369260. modest efficacy lymphoma mouse model following oral dosing. Conclusions: represents excellent tool function human cancer cells models. No conflict interest.