Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors

To
identify new chemical
series with enhanced binding affinity
to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket
adjacent to Val18. With no opportunities for strong polar interactions,
we focused on attaining close shape complementarity by ring fusion
onto our quinolinone lead series. Following exploration of different
sized rings, we identified a conformationally restricted core which
optimally filled the available space, leading to potent BCL6 inhibitors.
Through X-ray structure-guided design, combined with efficient synthetic
chemistry to make the resulting novel core structures, a >300-fold
improvement in activity was obtained by the addition of seven heavy
atoms.