Hypomorph mutation-directed small-molecule protein-protein interaction inducers to restore mutant SMAD4-suppressed TGF-β signaling.

Abstract

Tumor suppressor genes represent a major class of oncogenic drivers. However, direct targeting of loss-of-function tumor suppressors remains challenging. To address this gap, we explored a variant-directed chemical biology approach to reverse the lost function of tumor suppressors using SMAD4 as an example. SMAD4, a central mediator of the TGF-β pathway, is recurrently mutated in many tumors. Here, we report the development of a TR-FRET technology that recapitulated the dynamic differential interaction of SMAD4 and SMAD4R361H with SMAD3 and identified Ro-31-8220, a bisindolylmaleimide derivative, as a SMAD4R361H/SMAD3 interaction inducer. Ro-31-8220 reactivated the dormant SMAD4R361H-mediated transcriptional activity and restored TGF-β-induced tumor suppression activity in SMAD4 mutant cancer cells. Thus, demonstration of Ro-31-8220 as a SMAD4R361H/SMAD3 interaction inducer illustrates a general strategy to reverse the lost function of tumor suppressors with hypomorph mutations and supports a systematic approach to develop small-molecule protein-protein interaction (PPI) molecular glues for biological insights and therapeutic discovery.

• Authors: Cong Tang, Xiulei Mo, Qiankun Niu, Alafate Wahafu, Xuan Yang, Min Qui, Andrey A Ivanov, Yuhong Du, Haian Fu
• Journal: Cell chemical biology (Cell Chem Biol) Vol. 28 Issue 5 Pg. 636-647.e5 (05 20 2021) ISSN: 2451-9448 [Electronic] United States
• PMID: 33326750 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Indoles
• SMAD4 protein, human
• Smad4 Protein
• Small Molecule Libraries
• Transforming Growth Factor beta
• Ro 31-8220

Topics

• Cell Line
• Female
• Fluorescence Resonance Energy Transfer
• Genes, Tumor Suppressor
• Humans
• Indoles (chemistry, metabolism)
• Male
• Protein Binding
• Signal Transduction (genetics)
• Smad4 Protein (chemistry, genetics, metabolism)
• Small Molecule Libraries (chemistry, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)