PB1 is a bromodomain-containing
protein hypothesized to act as
the nucleosome-recognition subunit of the PBAF complex. Although PB1
is a key component of the PBAF chromatin remodeling complex, its exact
role has not been elucidated due to the lack of potent and selective
inhibitors. Chemical probes that target specific bromodomains within
the complex would constitute highly valuable tools to characterize
the function and therapeutic pertinence of PB1 and of each of its
bromodomains. Here, we report the design and synthesis of lead compound
LM146
, which displays strong stabilization of the second and
fifth bromodomains of PB1 as shown by DSF.
LM146
does
not interact with bromodomains outside of sub-family VIII and binds
to PB1(2), PB1(5), and SMARCA2B with
K
D
values of 110, 61, and 2100 nM, respectively, providing a ∼34-fold selectivity profile for PB1(5)
over SMARCA2.
The YAP-TEAD transcriptional complex is responsible for the expression of genes that regulate cancer cell growth and proliferation. Dysregulation of the Hippo pathway due to overexpression of TEAD has been reported in a wide range of cancers. Inhibition of TEAD represses the expression of associated genes, demonstrating the value of this transcription factor for the development of novel anti-cancer therapies. We report herein the design, synthesis and biological evaluation of LM98, a flufenamic acid analogue. LM98 shows strong affinity to TEAD, inhibits its autopalmitoylation and reduces the YAP-TEAD transcriptional activity. Binding of LM98 to TEAD was supported by 19 F-NMR studies while co-crystallization experiments confirmed that LM98 is anchored within the palmitic acid pocket of TEAD. LM98 reduces the expression of CTGF and Cyr61, inhibits MDA-MB-231 breast cancer cell migration and arrests cell cycling in the S phase during cell division.
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