Development of UM-200: A Novel Alkyne Amide-Based Inhibitor of the cGAS-STING Pathway

In response to double
stranded DNA (dsDNA), the cGAS-STING pathway
activates the innate immune response. While beneficial for detecting
invading bacteria and viruses, overactivation of this pathway is associated
with the development of several inflammatory and autoimmune diseases,
making STING an attractive therapeutic target. Previously, we reported
STING inhibitors that employ a nitrofuran warhead; these compounds
covalently modify STING and prevent its oligomerization. Herein we
describe our efforts to identify alternative electrophilic warheads
using UM-001 as a starting scaffold. These efforts led
to UM-200, a next-generation inhibitor featuring an alkyne
amide warhead. UM-200 potently suppresses STING signaling
in murine and human systems, retains activity against the prevalent
human STING variant (R232), and effectively inhibits pathway activation
in primary human CD14+ monocytes. Notably, UM-200 exhibits
markedly improved metabolic stability compared to earlier analogs.
These findings position UM-200 as a promising scaffold
for developing therapeutics targeting STING-driven inflammatory and
autoimmune disorders.