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Home > Discovery of the first chemical tools to regulate MKK3-mediated MYC activation in cancer

Discovery of the first chemical tools to regulate MKK3-mediated MYC activation in cancer [1]

Yang et al. (2021) Bioorg Med Chem. CC BY-NC-ND 4.0

Yang et al. (2021) Bioorg Med Chem. CC BY-NC-ND 4.0

Yang X, Fan D, Troha AH, Ahn HM, Qian K, Liang B, Du Y, Fu H, Ivanov AA.

Bioorganic & Medicinal Chemistry

July 22, 2021

The transcription master regulator MYC plays an essential role in regulating major cellular programs and is a well-established therapeutic target in cancer. However, MYC targeting for drug discovery is challenging. New therapeutic approaches to control MYC-dependent malignancy are urgently needed. The mitogen-activated protein kinase kinase 3 (MKK3) binds and activates MYC in different cell types, and disruption of MKK3-MYC protein-protein interaction may provide a new strategy to target MYC-driven programs. However, there is no perturbagen available to interrogate and control this signaling arm. In this study, we assessed the drugability of the MKK3-MYC complex and discovered the first chemical tool to regulate MKK3-mediated MYC activation. We have designed a short 44-residue inhibitory peptide and developed a cell lysate-based time-resolved fluorescence resonance energy transfer (TR-FRET) assay to discover the first small molecule MKK3-MYC PPI inhibitor. We have optimized and miniaturized the assay into an ultra-high-throughput screening (uHTS) 1536-well plate format. The pilot screen of ~6,000 compounds of a bioactive chemical library followed by multiple secondary and orthogonal assays revealed a quinoline derivative SGI-1027 as a potent inhibitor of MKK3-MYC PPI. We have shown that SGI-1027 disrupts the MKK3-MYC complex in cells and in vitro and inhibits MYC transcriptional activity in colon and breast cancer cells. In contrast, SGI-1027 does not inhibit MKK3 kinase activity and does not interfere with well-known MKK3-p38 and MYC-MAX complexes. Together, our studies demonstrate the drugability of MKK3-MYC PPI, provide the first chemical tool to interrogate its biological functions, and establish a new uHTS assay to enable future discovery of potent and selective inhibitors to regulate this oncogenic complex.

https://pubmed.ncbi.nlm.nih.gov/34333394/ [2]
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Source URL:https://ocg.cancer.gov/news-publications/publications/discovery-first-chemical-tools-regulate-mkk3

Links
[1] https://ocg.cancer.gov/news-publications/publications/discovery-first-chemical-tools-regulate-mkk3 [2] https://pubmed.ncbi.nlm.nih.gov/34333394/