Programmable protein degraders enable selective knockdown of pathogenic β-catenin subpopulations in vitro and in vivo.

Authors

Tianzheng Ye, Azmain Alamgir, Cara M Robertus, Darianna Colina, Connor Monticello, Thomas Connor Donahue, Chandra Bandi, Lauren Hong, Sophia Vincoff, Shrey Goel, Kieu Lam, James Heyes, David Putnam, Christopher A Alabi, Pranam Chatterjee, Matthew P DeLisa

Published in

Science advances. Volume 12. Issue 35. Pages eaec8271. Aug 28, 2026. Epub Aug 28, 2026.

Abstract

Aberrant activation of Wnt signaling results in unregulated accumulation of cytosolic β-catenin, which subsequently enters the nucleus and promotes transcription of genes that contribute to cellular proliferation and malignancy. Here, we sought to eliminate pathogenic β-catenin from the cytosol using designer ubiquibodies (uAbs), chimeric proteins composed of an E3 ubiquitin ligase and a target-binding domain that redirect intracellular proteins to the proteasome for degradation. To accelerate uAb development, we leveraged a protein language model-driven algorithm called SaLT&PepPr to computationally design "guide" peptides with affinity for β-catenin, which were subsequently fused to the catalytic domain of a human E3 called carboxyl terminus of Hsp70-interacting protein. Expression of the resulting peptide-guided uAbs in colorectal cancer cells led to the identification of several designs that greatly reduced the abnormally stable pool of free β-catenin in the cytosol and nucleus while preserving the normal membrane-associated subpopulation. This selective knockdown of pathogenic β-catenin suppressed Wnt/β-catenin signaling and impaired tumor cell survival and proliferation. Furthermore, one of the best degraders selectively decreased cytosolic but not membrane-associated β-catenin levels in livers of BALB/c mice following delivery as a lipid nanoparticle-encapsulated mRNA. Collectively, these findings reveal the unique ability of uAbs to selectively deplete abnormal proteins in vitro and in vivo and open the door to peptide-programmable biologic modulators of other disease-causing proteins.

PMID:
42664344
Bibliographic data and abstract were imported from PubMed on 29 Aug 2026.

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