Fig. 1: The BRD9 degrader, QA-68-ZU81, shows increased potency and selectivity versus BRD9 inhibitors.
From: BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma
A Structure-based drug design evolves chemical matter from selective binding domain (BD) inhibitor, EA-89-YM35 (“EA-89”), to selective BD degrader, QA-68-ZU81 (“QA-68”). X-ray co-crystal shows binding mode of EA-89 on BRD9 at 1.76 Angstroms making extended interactions across the surface of BRD9 with thienopyridone docking into the acetyl lysine pocket. B The BRD9 degrader, QA-68, provides an >100-fold increase in potency versus the matched inhibitor, EA-89. 7-day assay. C Effects of BRD9 degrader treatment on BRD9 expression in MV4-11 cells. D, upper panel Comparison of effects of QA-68 and EA-89 on BRD9, c-MYC and c-MYB expression in SKM-1 cells. 24-h assay. D, lower panel Comparison of effects of QA-68 and dBRD9-A on BRD9 expression. 6-day assay. E–H Effects of QA-68 or dBRD9-A treatment on BRD9, c-Myc and c-Myb expression in MV4-11 (E), Kasumi-1-luc + (F), HEL (G) and K052 (H). 24-h assay.
