1. Academic Validation
  2. The discovery of potent small molecule activators of human STING

The discovery of potent small molecule activators of human STING

  • Eur J Med Chem. 2021 Jan 1;209:112869. doi: 10.1016/j.ejmech.2020.112869.
David C Pryde 1 Sandip Middya 2 Monali Banerjee 2 Ritesh Shrivastava 2 Sourav Basu 2 Rajib Ghosh 2 Dharmendra B Yadav 2 Arjun Surya 2
Affiliations

Affiliations

  • 1 Curadev Pharma Ltd, Innovation House, Discovery Park, Ramsgate Road, Sandwich, Kent, CT13 9ND, UK. Electronic address: david@curadev.co.uk.
  • 2 Curadev Pharma Pvt. Ltd, B-87, Sector 83, Noida 201305, Uttar Pradesh, India.
Abstract

The adaptor protein STING plays a major role in innate immune sensing of cytosolic nucleic acids, by triggering a robust interferon response. Despite the importance of this protein as a potential therapeutic target for serious unmet medical conditions including Cancer and infectious disease there remains a paucity of STING ligands. Starting with a benzothiazinone series of weak STING activators (human EC50 ∼10 μM) we identified several chemotypes with sub-micromolar STING activity across all the major protein polymorphs. An example compound 53 based on an oxindole core structure demonstrated robust on-target functional activation of STING (human EC50 185 nM) in immortalised and primary cells and a cytokine induction fingerprint consistent with STING activation. Our study has identified several related series of potent small molecule human STING activators with potential to be developed as immunomodulatory therapeutics.

Keywords

Cytokines; Immunotherapy; Interferon genes; STING.

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