Senior Director Exo Therapeutics North Grafton, Massachusetts, United States
Abstract Text: Aberrant activation of cGAS-STING-TBK1 pathway via excessive production of pro-inflammatory cytokines is linked to several autoimmune diseases including monogenic diseases like AGS (Aicardi-Goutières syndrome) and SAVI (STING-associated vasculopathy with onset in infancy). Publications support importance of this pathway in lupus, SLE, CLE, and other autoimmune disorders such as Systemic Scleroderma. To overcome the existing challenges to inhibit this pathway, we have generated novel “exosite” inhibitors of TBK1 (EXO-TBKi), that disrupt recruitment by STING for downstream activation of interferon and NF-κB responses. EXO-TBKi selectively inhibit the TBK1-STING axis while sparing non-disease relevant housekeeping functions of the kinase, offering superior efficacy and improved therapeutic window. Rational and structure-based drug discovery efforts resulted in identification of a series of selective EXO-TBKi with potent binding affinities that translated into nanomolar inhibition of IFNβ in THP1 cells and primary human cell types. Orally bioavailable EXO-TBKi were evaluated in both in vivo and ex vivo models to inhibit proximal and distal pharmacodynamic markers upon stimulation with a STING agonist. We also observe this PK/PD relationship in a pathway-driven TREX-1KO model where treatment with EXO-TBKi results in dramatic reduction of pro-inflammatory cytokines including IFNβ, CXCL-10, CXCL-9 and IFIT1. Most strikingly, when assessed for activity in SLE patient derived human whole blood and PBMC, EXO-TBKi robustly suppresses pathway activation. Similarly, upon activation of pathway, EXO-TBKi reduces cytokine production in disease relevant skin inflammatory models, fibroblasts and keratinocytes. In summary, we have identified potent, selective EXO-TBK1 inhibitors, demonstrated efficacy across pre-clinical models and optimized properties towards developmental candidate nomination.
