FT-6876, a Potent and Selective Inhibitor of CBP/p300, is Active in Preclinical Models of Androgen Receptor-Positive Breast Cancer

  • Target Oncol. 2023 Feb 24. doi: 10.1007/s11523-023-00949-7.
Maureen Caligiuri  1 ,  Grace L Williams  1 ,  Jennifer Castro  1 ,  Linda Battalagine  1 ,  Erik Wilker  1 ,  Lili Yao  1 ,  Shawn Schiller  1 ,  Angela Toms  1 ,  Ping Li  1 ,  Eneida Pardo  1 ,  Bradford Graves  1 ,  Joey Azofeifa  2 ,  Agustin Chicas  1 ,  Torsten Herbertz  1 ,  Maria Lai  2 ,  Joel Basken  2 ,  Kenneth W Wood  1 ,  Qunli Xu  1 ,  Sylvie M Guichard  3
Affiliations
  • 1. Forma Therapeutics, Inc, 300 N Beacon St, Watertown, MA, 02472, USA.
  • 2. Arpeggio Bio, Boulder, CO, USA.
  • 3. Forma Therapeutics, Inc, 300 N Beacon St, Watertown, MA, 02472, USA. [email protected].
PMID: 36826464 DOI: 10.1007/s11523-023-00949-7
Abstract

Background: Patients with triple-negative breast Cancer (TNBC) expressing the Androgen Receptor (AR) respond poorly to neoadjuvant chemotherapy, although AR antagonists have shown promising clinical activity, suggesting these tumors are AR-dependent. cAMP responsive element binding protein (CREB)-binding protein (CBP) and p300 are transcriptional co-activators for the AR, a key driver of AR+ breast and prostate Cancer, and may provide a novel therapeutic target in AR+ TNBC.

Objectives: The aim of this study was to determine the therapeutic potential of FT-6876, a new CBP/p300 bromodomain inhibitor, in breast Cancer models with a range of AR levels in vitro and in vivo.

Methods: Effects of FT-6876 on the CBP/p300 pathway were determined by combining chromatin immunoprecipitation (ChIP) with precision run-on Sequencing (PRO-seq) complemented with H3K27 acetylation (Ac) and transcriptional profiling. The antiproliferative effect of FT-6876 was also measured in vitro and in vivo.

Results: We describe the discovery of FT-6876, a potent and selective CBP/p300 bromodomain inhibitor. The combination of ChIP and PRO-seq confirmed the reduction in H3K27Ac at specific promoter sites concurrent with a decrease in CBP/p300 on the chromatin and a reduction in nascent RNA and enhancer RNA. This was associated with a time- and concentration-dependent reduction in H3K37Ac associated with a decrease in AR and Estrogen receptor (ER) target gene expression. This led to a time-dependent growth inhibition in AR+ models, correlated with AR expression. Tumor growth inhibition was also observed in AR+ tumor models of TNBC and ER+ breast Cancer subtypes with consistent pharmacokinetics and pharmacodynamics.

Conclusion: Our findings demonstrate FT-6876 as a promising new CBP/p300 bromodomain inhibitor, with efficacy in preclinical models of AR+ breast Cancer.

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