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

An expanded universe of cancer targets

“…These new targets are the consequence of tumor heterogeneity and represent non-oncogene-dependent cancer vulnerabilities, which inform new types of therapeutic opportunities. as a result of tumor suppressor mutations (Tang et al, 2020). This study identified a bisindolylmaleimide derivative that restored interaction between mutated SMAD4 and SMAD3 and reactivated the cell growth suppression function of the SMAD4/ SMAD3 complex.…”

How do you mend inactive tumor suppressor mutants? You glue them!

“…Mounting clinical evidence frames TGF-b as a tumorderived immunosuppressor, an inducer of tumor mitogens, and an enabler of pro-metastatic cytokine secretion (Batlle and Massagué , 2019). In this issue of Cell Chemical Biology, Tang et al (2020) sought to identify small molecules to restore the cytostatic activity of TGF-b as anti-cancer therapies. Upon TGF-b stimulation, SMAD4 (a common partner SMAD, or co-SMAD) forms a complex with the TGF-b receptor-phosphorylated proteins SMAD2 or SMAD3 (the receptor-specific SMADs, or R-SMADs), translocates to the nucleus, and modulates gene expression to carry out various cellular responses (Figure 1) (Massagué , 2012).…”

“…Unlike oncoproteins, however, tumor suppressors have been considered ''undruggable'' targets because of the formidable task of using small molecules to restore faulty PPIs in comparison, for example, to inhibiting the enzymatic reaction of a kinase. Undaunted, Tang and colleagues launched a high-throughput screen (HTS) of over 2,000 compounds to successfully identify two bisindolylmaleimide compounds-Ro-31-8220 and Go-6983-that increase the PPI between SMAD4 R361H and SMAD3 (hereafter referred to as SMAD4: SMAD3 glues) (Tang et al, 2020). Interestingly, the SMAD4:SMAD3 glues also facilitated the interaction between SMAD4 D351H mutant and SMAD3 (Tang et al, 2020), implying their effectiveness in cancer cells harboring a variety of SMAD4 mutations that affect the PPI with SMAD3.…”

“…Undaunted, Tang and colleagues launched a high-throughput screen (HTS) of over 2,000 compounds to successfully identify two bisindolylmaleimide compounds-Ro-31-8220 and Go-6983-that increase the PPI between SMAD4 R361H and SMAD3 (hereafter referred to as SMAD4: SMAD3 glues) (Tang et al, 2020). Interestingly, the SMAD4:SMAD3 glues also facilitated the interaction between SMAD4 D351H mutant and SMAD3 (Tang et al, 2020), implying their effectiveness in cancer cells harboring a variety of SMAD4 mutations that affect the PPI with SMAD3. The SMAD4:SMAD3 glues did not seem to make SMAD4 ''sticky,'' as they did not induce a PPI between SMAD4 and the bone morphogenetic protein (BMP) signaling R-SMADs-SMAD1/5/8, for example (Tang et al, 2020).…”

“…Interestingly, the SMAD4:SMAD3 glues also facilitated the interaction between SMAD4 D351H mutant and SMAD3 (Tang et al, 2020), implying their effectiveness in cancer cells harboring a variety of SMAD4 mutations that affect the PPI with SMAD3. The SMAD4:SMAD3 glues did not seem to make SMAD4 ''sticky,'' as they did not induce a PPI between SMAD4 and the bone morphogenetic protein (BMP) signaling R-SMADs-SMAD1/5/8, for example (Tang et al, 2020). Although TGF-b stimulation did not inhibit the colony formation of colon carcinoma HCT116 cells harboring SMAD4 R361H , the cells treated with the SMAD4:SMAD3 glue formed fewer colonies in response to TGF-b, indicating the successful restoration of the cytostatic activity of TGF-b by the SMAD4:SMAD3 glue (Tang et al, 2020).…”