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SUMOylation, the covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to protein substrates, has been reported to suppress type I interferon (IFN1) responses. TAK-981, a selective small-molecule inhibitor of SUMOylation, pharmacologically reactivates IFN1 signaling and immune responses against cancers. In vivo treatment of wild-type mice with TAK-981 up-regulated IFN1 gene expression in blood cells and splenocytes. Ex vivo treatment of mouse and human dendritic cells promoted their IFN1-dependent activation, and vaccination studies in mice demonstrated stimulation of antigen cross-presentation and T cell priming in vivo. TAK-981 also directly stimulated T cell activation, driving enhanced T cell sensitivity and response to antigen ex vivo. Consistent with these observations, TAK-981 inhibited growth of syngeneic A20 and MC38 tumors in mice, dependent upon IFN1 signaling and CD8+ T cells, and associated with increased intratumoral T and natural killer cell number and activation. Combination of TAK-981 with anti-PD1 or anti-CTLA4 antibodies improved the survival of mice bearing syngeneic CT26 and MC38 tumors. In conclusion, TAK-981 is a first-in-class SUMOylation inhibitor that promotes antitumor immune responses through activation of IFN1 signaling. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with solid tumors and lymphomas.


Eric S Lightcap, Pengfei Yu, Stephen Grossman, Keli Song, Mithun Khattar, Kristina Xega, Xingyue He, James M Gavin, Hisashi Imaichi, James J Garnsey, Erik Koenig, Hongru Zhang, Zhen Lu, Pooja Shah, Yu Fu, Michael A Milhollen, Beryl A Hatton, Jessica Riceberg, Vaishali Shinde, Cong Li, James Minissale, Xiaofeng Yang, Dylan England, Richard A Klinghoffer, Steve Langston, Katherine Galvin, Gary Shapiro, Sai M Pulukuri, Serge Y Fuchs, Dennis Huszar. A small-molecule SUMOylation inhibitor activates antitumor immune responses and potentiates immune therapies in preclinical models. Science translational medicine. 2021 Sep 15;13(611):eaba7791

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PMID: 34524860

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