Discovery of TBL1 Inhibitors as Anticancer Agents Targeting the Wnt Signaling Pathway
Introduction
Tegavivint is a novel small molecule inhibitor of the TBL1 protein family. TBL1 has been found to be a critical component of the beta catenin signaling pathway, and hence to play a vital role in tumor growth, and metastasis. Tegavivint binds directly to TBL1, disrupts the interaction with beta catenin, and inhibits the activation complex necessary for oncogenic activity, ultimately leading to the degradation of nuclear beta-catenin. This is of particular significance as increased expression of beta-catenin and TBL1 has been linked to metastasis and poor prognosis across a diverse spectrum of cancers. Tegavivint has successfully demonstrated good safety and clinical activity in a Phase 1 Proof of Concept clinical study focused on desmoid tumors, a rare sarcoma driven primarily by beta-catenin activating mutations. In addition, tegavivint is currently in clinical trials in AML, NSCLC, DLBCL, and pediatric cancers. Our drug discovery program at Iterion Therapeutics seeks to find second-generation orally bioavailable TBL1 inhibitors that leverage our experience with TBL1 as an oncology target.
Methods
Our knowledge of TBL1 and Tegavivint interactions combined with protein structure data of TBL1 provides us with a means to perform in-silico virtual screening to identify novel drug candidates. Using in-silico modeling of Tegavivint bound to TBL1, we developed several computational models. A combined approach of structure and ligand-based drug design was utilized. A combination of docking and MMGBSA simulations was used for a structure-based drug design approach. A ligand-based drug design approach using Tegavivint which encompassed shape screening, pharmacophore modeling, and QSAR modeling based upon established activity of an in-house library of Tegavivint analogs. Three different pharmacophore models were also built selecting different features from docked poses of Tegavivint. Hit follow-up via a screening cascade designed to characterize prospective hits for binding to TBL1 and activity in cancer cells has been implemented.
Results
The computational models were used for virtual screening of a series of compound libraries to identify virtual hit compounds. Virtual hit compounds were then acquired and validated using a direct binding assay to recombinant TBL1. Primary assay screening of selected virtual hits resulted in active compounds with ~2% hit rate. Compound series with predicted drug like properties were selected and analogs obtained by both computational methods and by chemical synthesis. Validated hits were further optimized using iterative process of 'design - syntesize - test' based on preliminary SAR studies and assay insights.
Conclusion
The drug discovery program at Iterion Therapeutics seeks to find a second-generation TBL1 inhibitor that leverages our current understanding of TBL1 as an oncology target. The goal of this program is to identify novel, structurally distinct drug candidates with improved pharmaceutical properties, and robust oral bioavailability. Further understanding of the role of new compounds in TBL1 mediated pathways will help us to focus on TBL1 inhibition in targeted patient populations as anticancer therapy.