CCT369260 is an Orally Avtive B-cell Lymphoma 6 (BCL6) Inhibitor with Anti-Tumor Activity
Posted On 2020-11-03
BCL6 (B-cell lymphoma 6 protein) is a transcriptional repressor. Strikingly, this protein plays a key role in the formation and maintenance of germinal centers during the process of antibody affinity maturation. In addition, BCL6 represses genes involved in cell death, differentiation, and the DNA damage response. Most B-cell lymphomas arise from germinal center B-cells. Recruitment of co-repressors is essential for the repressive and oncogenic functions of BCL6, and disruption of this interaction is sufficient to inhibit lymphoma cell growth. Hence, the scientists sought to discover compounds that disrupt the PPI between the BTB domain of BCL6. And its co-repressors to alleviate BCL6-mediated gene repression, inhibit lymphoma cell growth, and identify new treatments for BCL6-driven lymphomas. Eventually, the team discovered and identified CCT369260 as a B-cell lymphoma 6 (BCL6) degrader.
In vivo, in OCI-Ly1 DLBCL xenograft model (female SCID mice), CCT369260 with oral dosing (compound 1, 15 mg/kg, po, single dose) decreased the levels of BCL6 in the tumor observed up to 10 h after administration.
Not only that, but pharmacokinetic analysis also shows that CCT369260 (CCT369260) demonstrated moderate clearance (CL 20 mL min<sup>−1</sup> kg<sup>−1</sup>) with mean oral bioavailability of 54%.
Moreover, CCT369260 shows sub-100 nM activity in a degradation assay in SU-DHL-4 cells, and robust antiproliferative activity, in common with previously identified degraders but in contrast to BCL6-targeting PROTACs.
As a non-PROTAC protein degrader, CCT369260 has the potential for lymphoma study. CCT369260 was progressed into PK studies. And the levels of compound needed to mediate degradation could be achieved in vivo following oral dosing. CCT369260 and the use of our BCL6 degraders validate BCL6 as a target for the treatment of hematological cancer.
Benjamin R Bellenie, et al. Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders. J Med Chem. 2020 Apr 23;63(8):4047-4068.