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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.

journal_name

Cell Chem Biol

journal_title

Cell chemical biology

authors

Tang C,Mo X,Niu Q,Wahafu A,Yang X,Qui M,Ivanov AA,Du Y,Fu H

doi

10.1016/j.chembiol.2020.11.010

subject

Has Abstract

pub_date

2020-12-04 00:00:00

eissn

2451-9456

issn

2451-9448

pii

S2451-9456(20)30473-6

pub_type

杂志文章

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