COMPOUND 2 is a first-in-class small molecule cGAMP competitive oral STING antagonist that reduces neuroinflammation in mouse models

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Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B592
Abstract ID: 7981

Presenting Author:
Monali Banerjee , Vice President, R&D at Curadev, Curadev

Abstract:

Background: Aberrant activation of the cGAS/STING pathway has been implicated in chronic inflammatory conditions such as neuroinflammation. Emerging evidence reveals that the cGAS-STING-mediated Type I interferon (IFN) signaling axis contributes to neuroinflammation and dopaminergic neurodegeneration in Parkinson's Disease (PD).   COMPOUND 2 is a novel cGAMP competitive synthetic small molecule STING antagonist discovered at Curadev.   Materials and Methods: Competitive binding was established using radioligand binding assays.  The neuroprotective effects of COMPOUND 2 were demonstrated in MPTP treated mice.  PK and plasma to brain partitioning of COMPOUND 2 was estimated after oral dosing in mice. Results:  COMPOUND 2 inhibits the binding of cGAMP to STING and causes reductions in the level of Type I interferons and pro-inflammatory cytokines from immune cells as well as in mice treated with a STING agonist.   There is significant partitioning of COMPOUND 2 into the brain after oral dosing.  Once a day oral administration of COMPOUND 2 provided protection from neurodegeneration, decreased striatal tyrosine hydroxylase expression and led to a recovery in dopamine levels in MPTP treated mice.  Conclusions: COMPOUND 2 is an orally administered novel first-in-class cGAMP competitive STING antagonist with high levels of brain exposure and is a promising candidate for the treatment of neuroinflammatory conditions.