2. Academic Validation
  3. Discovery of IACS-8803 and IACS-8779, potent agonists of stimulator of interferon genes (STING) with robust systemic antitumor efficacy

Discovery of IACS-8803 and IACS-8779, potent agonists of stimulator of interferon genes (STING) with robust systemic antitumor efficacy

  • Bioorg Med Chem Lett. 2019 Oct 15;29(20):126640. doi: 10.1016/j.bmcl.2019.126640.
Casey R Ager 1,  Huaping Zhang 2,  Zhanlei Wei 2,  Philip Jones 3,  Michael A Curran 1,  M Emilia Di Francesco 4
Affiliations

Affiliations

  • 1 Department of Immunology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blv., Houston 77030, TX, USA; The University of Texas MD Anderson UTHealth Graduate School of Biochemical Sciences, Immunology Program, 1515 Holcombe Blv., Houston 77030, TX, USA.
  • 2 WuXi AppTec (Wuhan) Co., Ltd., 666 Gaoxin Road, Wuhan East Lake High-tech Development Zone, Hubei 430075, China.
  • 3 Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blv., Houston 77030, TX, USA.
  • 4 Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blv., Houston 77030, TX, USA. Electronic address: [email protected].
PMID: 31500996 DOI: 10.1016/j.bmcl.2019.126640
Abstract

Activation of the stimulator of interferon genes (STING) pathway by both exogenous and endogenous cytosolic DNA results in the production of interferon beta (IFN-β) and is required for the generation of cytotoxic T-cell priming against tumor antigens. In the clinical setting, pharmacological stimulation of the STING pathway has the potential to synergize with immunotherapy Antibodies by boosting anti-tumor immune responses. We report the discovery of two highly potent cyclic dinucleotide STING agonists, IACS-8803 and IACS-8779, which show robust activation of the STING pathway in vitro and a superior systemic anti-tumor response in the B16 murine model of melanoma when compared to one of the clinical benchmark compounds.

Keywords

Cyclic dinucleotide; Immune response; Phosphorothioate esters; STING agonists; T-cell priming.

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