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ID: ALA4828734
Journal: J Med Chem
Title: Discovery of High-Affinity Inhibitors of the BPTF Bromodomain.
Authors: Lu T, Lu H, Duan Z, Wang J, Han J, Xiao S, Chen H, Jiang H, Chen Y, Yang F, Li Q, Chen D, Lin J, Li B, Jiang H, Chen K, Lu W, Lin H, Luo C.
Abstract: The dysfunctional bromodomain PHD finger transcription factor (BPTF) exerts a pivotal influence in the occurrence and development of many human diseases, particularly cancers. Herein, through the structural decomposition of the reported BPTF inhibitor TP-238, the effective structural fragments were synthetically modified to obtain our lead compound DC-BPi-03. DC-BPi-03 was identified as a novel BPTF-BRD inhibitor with a moderate potency (IC50 = 698.3 ± 21.0 nM). A structure-guided structure-activity relationship exploration gave rise to two BPTF inhibitors with much higher affinities, DC-BPi-07 and DC-BPi-11. Notably, DC-BPi-07 and DC-BPi-11 show selectivities 100-fold higher than those of other BRD targets. The cocrystal structures of BPTF in complex with DC-BPi-07 and DC-BPi-11 demonstrate the rationale of chemical efforts from the atomic level. Further study showed that DC-BPi-11 significantly inhibited leukemia cell proliferation.
CiteXplore: 34375106