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.
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.
B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and in vivo exposure of the non-degrading isomer, CCT373567, of our recently published degrader, CCT373566. The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. 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.
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