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  3. 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

  • Bioorg Med Chem. 2021 Sep 1:45:116324. doi: 10.1016/j.bmc.2021.116324.
Xuan Yang 1,  Dacheng Fan 1,  Aidan Henry Troha 2,  Hyunjun Max Ahn 2,  Kun Qian 1,  Bo Liang 2,  Yuhong Du 3,  Haian Fu 4,  Andrey A Ivanov 5
Affiliations

Affiliations

  • 1 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Emory University, Atlanta, GA, USA; Emory Chemical Biology Discovery Center, Emory University School of Medicine, Emory University, Atlanta, GA, USA.
  • 2 Department of Biochemistry, Emory University School of Medicine, Emory University, Atlanta, GA, USA.
  • 3 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Emory University, Atlanta, GA, USA; Emory Chemical Biology Discovery Center, Emory University School of Medicine, Emory University, Atlanta, GA, USA; Winship Cancer Institute, Emory University, Atlanta, GA, USA.
  • 4 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Emory University, Atlanta, GA, USA; Emory Chemical Biology Discovery Center, Emory University School of Medicine, Emory University, Atlanta, GA, USA; Winship Cancer Institute, Emory University, Atlanta, GA, USA; Department of Hematology & Medical Oncology Emory University, Atlanta, GA, USA. Electronic address: hfu@emory.edu.
  • 5 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Emory University, Atlanta, GA, USA; Emory Chemical Biology Discovery Center, Emory University School of Medicine, Emory University, Atlanta, GA, USA; Winship Cancer Institute, Emory University, Atlanta, GA, USA. Electronic address: andrey.ivanov@emory.edu.
PMID: 34333394 DOI: 10.1016/j.bmc.2021.116324
Abstract

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.

Keywords

Chemical tool; High-throughput screening; MKK3; MYC; Oncogenic signaling; Protein–protein interaction; Small molecule inhibitor.

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