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Article Abstract
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 exposure of the non-degrading isomer, , of our recently published degrader, . 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 , a potent inhibitor of BCL6 with a good profile. Modest efficacy was achieved in a lymphoma xenograft mouse model after oral dosing.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150366 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.3c00155 | DOI Listing |
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