Selective and Cell-Active PBRM1 Bromodomain Inhibitors Discovered through NMR Fragment Screening

PBRM1 is a subunit of the PBAF chromatin remodeling complex
that
uniquely contains six bromodomains. PBRM1 can operate as a tumor suppressor
or tumor promoter. PBRM1 is a tumor promoter in prostate cancer, contributing
to migratory and immunosuppressive phenotypes. Selective chemical
probes targeting PBRM1 bromodomains are desired to elucidate the association
between aberrant PBRM1 chromatin binding and cancer pathogenesis and
the contributions of PBRM1 to immunotherapy. Previous PBRM1 inhibitors
unselectively bind SMARCA2 and SMARCA4 bromodomains with nanomolar
potency. We used our protein-detected NMR screening pipeline to screen
1968 fragments against the second PBRM1 bromodomain, identifying 17
hits with Kd values from 45 μM to
>2 mM. Structure–activity relationship studies on the tightest-binding
hit resulted in nanomolar inhibitors with selectivity for PBRM1 over
SMARCA2 and SMARCA4. These chemical probes inhibit the association
of full-length PBRM1 to acetylated histone peptides and selectively
inhibit growth of a PBRM1-dependent prostate cancer cell line.