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

• Type of Material: Article
• Authors: Cong Tang, Emory University; Xiulei Mo, Emory University; Qiankun Niu, Emory University; Alafate Wahafu, Emory University; Xuan Yang, Emory University; Min Qui, Emory University; Andrey Ivanov, Emory University; Yuhong Du, Emory University; Haian Fu, Emory University
• Language: English
• Date: 2021-05-20
• Publisher: CELL PRESS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Elsevier Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.chembiol.2020.11.010
• Title of Journal or Parent Work: CELL CHEMICAL BIOLOGY
• Volume: 28
• Issue: 5
• Start Page: 636
• End Page: +
• Keywords: INSIGHTS; CANCER; TUMOR-SUPPRESSOR; Life Sciences & Biomedicine; STRUCTURAL BASIS; TARGET; APOPTOSIS; Science & Technology; Biochemistry & Molecular Biology; SELECTIVE INHIBITORS; STABILIZATION; EXPRESSION; SMAD4 MUTATIONS

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.