P1/2, N=49, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

P1/2, N=49, Not yet recruiting, Boehringer Ingelheim

Consequently, A5 exhibited enhanced antiproliferative activity compared to the BCL6 inhibitor BI3812 and the BCL6 degrader BI3802, along with induction of cell cycle arrest and apoptosis. Furthermore, A5 significantly downregulated BCL6 and GSPT1 protein levels in vivo. Thus, this study provides a solid foundation for the development of novel multitarget BCL6 degraders with improved anti-lymphoma potential.

A19 induces rapid and efficient BCL6 degradation (DC50 = 34 pM in OCI-LY1 cells) and displays superior antiproliferative activity compared to the molecular glue BI3802 across multiple DLBCL cell lines...Further, oral dosing of A19 led to BCL6 degradation and inhibition of tumor growth in vivo. Overall, A19 is a valuable chemical tool and a promising lead compound toward the development of BCL6-dependent DLBCL.

Compound 15d demonstrated significant BCL6-SMRT inhibition with favorable physicochemical properties (Calculated LogP (ClogP) and topological polar surface area (tPSA)). These findings highlight the potential of pyrimidinediamine-based scaffolds as novel BCL6 inhibitors, warranting further structural optimization to improve their efficacy.

In conclusion, targeting BCL6 with 79-6 inhibits T and B cells' differentiation towards Tfh cells and plasma blasts and subsequent antibody production. Small molecule 79-6 is a promising compound which might prevent interaction between Tfh and B cells.

Further studies showed that WK692 inhibited the DLBCL growth without toxic effects in vivo and synergizes with the EZH2 and PRMT5 inhibitors. Our results demonstrated that WK692 as a BCL6 inhibitor may be developed as a novel potential anticancer agent against DLBCL.

CML cells with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors, BI-3812. Treatment of CML cells with BCL6 inhibitor and TKIs suggested enhanced anti-leukemia activity. In summary, our findings suggest BCL6 as a therapeutic target for the treatment of CML.

DLBCL mouse models were utilized to evaluate the therapeutic potential of combining chidamide and lenalidomide in vivo. Furthermore, BCL6 was a pivotal determinant of chidamide sensitivity and a reliable biomarker for treatment response. Integrating HDAC and BCL6 inhibition held potential for personalized and effective DLBCL treatments.

We further proved that WK499 and AraC could achieve a better result of inhibiting the growth of AML in vivo. These findings indicate that WK499, a small molecule inhibitor of BCL6, not only inhibits the proliferation of AML, but also provides an effective therapeutic strategy for increasing AML sensitivity to chemotherapy.

Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of CCT374705, a potent inhibitor of BCL6 with a good in vivo profile. Modest in vivo efficacy was achieved in a lymphoma xenograft mouse model after oral dosing.

Moreover, FX1 also inhibited the proportion and number of splenic plasma cells, germinal center B cells, IgG1 B cells, and the donor-specific antibody in recipient mice. We found BCL6 inhibitor FX1 protects chronic cardiac transplant rejection and inhibits the expansion of Tfh cells and the humoral response, which suggest that BCL6 is a potential therapeutic target of the treatment for chronic cardiac transplant rejection.