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The Small Molecule BC-2059 Inhibits Wingless/Integrated (Wnt)-Dependent Gene Transcription in Cancer through

Raffaella Soldi1, Tithi Ghosh Halder1, Samuel Sampson1

  • 1Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.).

The Journal of Pharmacology and Experimental Therapeutics
|May 19, 2021
PubMed

Insights

The Wnt signaling inhibitor BC-2059 targets the transducin beta-like 1 (TBL1)/beta-catenin complex. This selective disruption offers a potential therapeutic strategy for various cancers with deregulated Wnt pathways.

Area of Science:

  • Molecular Biology
  • Cancer Therapeutics
  • Signal Transduction

Background:

  • Aberrant Wnt signaling drives cancer development, making beta-catenin a key therapeutic target.
  • BC-2059 is a novel small-molecule inhibitor that induces apoptosis by disrupting the beta-catenin/transducin beta-like 1 (TBL1) complex.
  • The precise mechanism of BC-2059 action remained previously uncharacterized.

Purpose of the Study:

  • To elucidate the mechanism of action of the Wnt pathway inhibitor BC-2059.
  • To characterize the interaction between BC-2059, TBL1, and beta-catenin.
  • To determine the selectivity of BC-2059's inhibitory effects.

Main Methods:

  • Biochemical assays to assess protein complex interactions.
  • Site-directed mutagenesis to identify key amino acids in TBL1.
  • Computational modeling to predict drug-target interactions.
  • Assays to evaluate disruption of TBL1 interactions with other protein complexes.

Main Results:

  • BC-2059 directly binds to TBL1 with high affinity within the beta-catenin complex.
  • Two specific amino acids in a TBL1 hydrophobic pocket are crucial for beta-catenin binding.
  • Computational modeling indicated BC-2059 targets this same hydrophobic pocket on TBL1.
  • BC-2059 selectively disrupts the TBL1/beta-catenin interaction without affecting TBL1 interactions with NCoR/SMRT or NF-kappaB complexes.

Conclusions:

  • BC-2059 selectively targets and disrupts the TBL1/beta-catenin protein complex.
  • This targeted mechanism suggests BC-2059 as a promising therapeutic agent for cancers dependent on Wnt signaling.
  • The findings provide a mechanistic basis for BC-2059's efficacy in Wnt-driven tumors.

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