Nitrofuran-Based STING Inhibitors

Leonard Barasa; Leo DeOrsey; Maeve D O'Reilly; Shruti Choudhary; Sara E Cahill; Anukriti Mathur; Sakshi Rajoria; Robert Madison Green; Akumalla Allabaji; Shreekrishna Nellikkalaya; Sourav Paul; Srinivasa Rao Vidadala; Sujit Kumar Sarkar; Santoshkumar N Patil; Jeffrey Hale; Fiachra Humphries; Katherine A Fitzgerald; Paul R Thompson

doi:10.1021/acsomega.5c05578

Nitrofuran-Based STING Inhibitors

ACS Omega. 2025 Sep 4;10(36):41693-41706. doi: 10.1021/acsomega.5c05578. eCollection 2025 Sep 16.

Authors

Leonard Barasa^{1

2}, Leo DeOrsey^{1

2}, Maeve D O'Reilly^{1

2}, Shruti Choudhary^{1

2}, Sara E Cahill³, Anukriti Mathur³, Sakshi Rajoria^{1

2}, Robert Madison Green^{1

2}, Akumalla Allabaji⁴, Shreekrishna Nellikkalaya⁴, Sourav Paul⁴, Srinivasa Rao Vidadala⁴, Sujit Kumar Sarkar⁴, Santoshkumar N Patil⁴, Jeffrey Hale⁵, Fiachra Humphries³, Katherine A Fitzgerald³, Paul R Thompson^{1

2}

Affiliations

¹ Program in Chemical Biology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
² Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
³ Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
⁴ Syngene International Ltd., Bommasandra-Jigani Link Road, Biocon Park, Bangalore 560100, India.
⁵ Jeffrey Hale, Hale MedChem Advisors LLC, 233 Hazel Ave, Westfield, New Jersey 07090, United States.

Abstract

The cGAS-STING pathway plays a central role in the host response to foreign DNA. While cGAS-STING signaling is essential for antiviral immunity, aberrant STING activation is observed in amyotrophic lateral sclerosis (ALS), lupus, and autoinflammatory diseases such as Aicardi-Goutières syndrome (AGS) and STING associated vasculopathy with onset in infancy (SAVI). Thus, STING inhibitors are likely therapeutic agents. BB-Cl-amidine and LB244 are recently reported STING antagonists that work by blocking STING oligomerization. Herein, we describe the diverse strategies taken to optimize the potency of LB244. These efforts led to the development of UM-242 and UM-259. UM-242 and UM-259 both inhibit mouse and human STING-dependent signaling with efficacy similar to that of LB244. We further show that UM-242 and UM-259 maintain their potency against the most common human STING variant (R232) and inhibit STING signaling in primary human CD14+ monocytes. In summary, UM-242 and UM-259 represent additional novel scaffolds for the development of therapeutics to treat STING-dependent inflammatory diseases.