Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo .
Rosemary HuckvaleAlice C HarndenKwai-Ming J CheungOlivier A PierratRachel TalbotGary M BoxAlan T HenleyAlexis K de Haven BrandonAlbert E HallsworthMichael D BrightHafize Aysin AkpinarDaniel S J MillerDalia TarantinoSharon GowanAngela HayesEmma A GunnellAlfie BrennanOwen A DavisLouise D JohnsonSelby de KlerkCraig McAndrewYann-Vaï Le BihanMirco MeniconiRosemary BurkeVladimir KirkinRob L M van MontfortFlorence I RaynaudOlivia W RossaneseBenjamin R BellenieSwen HoelderPublished in: Journal of medicinal chemistry (2022)
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.