Design and synthesis of novel N-phenyl-4-pyrimidine-diamine BCL6 inhibitors with anti-tumor activities

Aim: To develop potent B cell lymphoma 6 (BCL6) inhibitors, novel N-phenyl-4-pyrimidine-diamine analogs were designed and synthesized via structure-based and computer-aided drug design. Methods: Starting from the hit compound ZB979, we synthesized three series of pyrimidinediamine BCL6 inhibitors (13a-13e, 14a-14c and 15a-15g) and evaluated their inhibitory activities on BCL6-SMRT interaction using homogeneous time-resolved fluorescence (HTRF) assays. The most promising candidate, compound 15d, was further assessed for its anti-proliferative activity and modulation of BCL6 downstream target genes, suppression of germinal center (GC) formation. Results: Compound 15d demonstrated significant BCL6-SMRT inhibition with favorable physicochemical properties (Calculated LogP (ClogP) and topological polar surface area (tPSA)). Conclusion: These findings highlight the potential of pyrimidinediamine-based scaffolds as novel BCL6 inhibitors, warranting further structural optimization to improve their efficacy.