Selective and Cell-Active PBRM1 Bromodomain Inhibitors Discovered through NMR Fragment Screening. J Med Chem 2022 Oct 27;65(20):13714-13735
Date
10/14/2022Pubmed ID
36227159Pubmed Central ID
PMC9630929DOI
10.1021/acs.jmedchem.2c00864Scopus ID
2-s2.0-85140311972 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
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.
Author List
Shishodia S, Nuñez R, Strohmier BP, Bursch KL, Goetz CJ, Olp MD, Jensen DR, Fenske TG, Ordonez-Rubiano SC, Blau ME, Roach MK, Peterson FC, Volkman BF, Dykhuizen EC, Smith BCAuthors
Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of WisconsinBrian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
CarcinogensChromatin
DNA Helicases
DNA-Binding Proteins
Histones
Humans
Male
Nuclear Proteins
Prostatic Neoplasms
Protein Domains
Transcription Factors
