What question did this study set out to answer?

The research aims to clarify the direct and indirect interactions of β-catenin within the WNT signaling pathway for better drug discovery.

April 5, 2026

Abstract 6413: MICRO-TAG® cell target engagement dissects direct and indirect effectors of β-catenin with functional readout

Key Points

The research aims to clarify the direct and indirect interactions of β-catenin within the WNT signaling pathway for better drug discovery.
Applied MICRO-TAG® Cell Target Engagement technology to evaluate 25 β-catenin/WNT effectors.
Used a real-time temperature series to measure ligand-dependent stabilization of β-catenin.
Conducted parallel assays like TOPFlash reporter activity to assess downstream signaling effects.
Successfully distinguished direct β-catenin binders from indirect effectors.
Quantified cellular target engagement potencies across multiple doses.
Established a scalable drug discovery system integrating target engagement with functional readouts.

Abstract

Abstract Transcription factors are challenging drug targets that require the native cellular environment for interrogation of direct engagement with potential therapeutic candidates. The transcription factor β-catenin is a therapeutically valuable yet challenging drug target, serving as signaling hub of the complex and highly interconnected WNT signaling network. Its central role and extensive pathway crosstalk have complicated efforts to distinguish effectors that bind β-catenin directly from those acting indirectly through upstream WNT components. This mechanistic distinction is critical for guiding rational drug discovery. We applied the MICRO-TAG® Cell Target Engagement technology to interrogate 25 reported β-catenin/WNT effectors. Using a novel direct target engagement system employing real-time temperature series, we quantified ligand-dependent stabilization of β-catenin across multiple doses, profiling their cellular target engagement potencies, under cellular conditions. Parallel functional assays, including TOPFlash reporter activity and WNT-responsive surface markers, integrated direct binding with downstream signaling readouts. This integrated approach distinguished direct β-catenin binders from effectors acting indirectly through upstream pathway components. By coupling cellular target engagement with functional readout, the MICRO-TAG® system enables scalable, mechanism-resolved drug discovery system for complex signaling pathways. This approach establishes a new paradigm for functionally interrogating therapeutic candidates through integrated target engagement and functional readout, within a unified, quantitative, and biologically relevant framework that is readily translatable to other challenging drug targets. Citation Format: Ivan Babic, Elmar Nurmemmedov. MICRO-TAG® cell target engagement dissects direct and indirect effectors of β-catenin with functional readout abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6413.

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