Discovery of cGAS Inhibitors for Interferon-Driven Autoimmune Diseases - SUMMARY
Cytoplasmic nucleic acids alert the immune system to invading pathogens and trigger a robust type I interferon
(IFN) response via activation of the STING (stimulator of interferon genes) receptor. The sensor for cytoplasmic
nucleic acids was recently discovered to be cyclic GMP-AMP synthase, an enzyme that produces a unique cyclic
dinucleotide second messenger, cGAMP, that serves as an agonist for the STING receptor. Aberrant activation
of the cGAS-STING pathway is rapidly emerging as an important
underlying cause of debilitating and sometimes fatal autoimmune
disorders including Aicardi–Goutieres Syndrome (AGS), a monogenic
encephalopathy that is usually fatal before adulthood, and systemic
lupus erythematosus (SLE). Development of cGAS inhibitors is clearly a
therapeutic strategy that should to be explored. There are no drugs
approved specifically for any of the IFN-driven autoimmune diseases,
and current IFN-targeted therapies in clinical development are mostly
biologicals; e.g., antibodies against IFNa or the type IFN receptor.
Inhibiting cGAS, the molecular trigger for type I IFN induction, is likely to
be more efficient than blocking downstream targets, and a small
molecule cGAS drug would have obvious advantages in terms of cost,
dosing and CNS exposure.
Aberrant activation of cGAS by dsDNA is the
trigger for a constitutive type I IFN
response, resulting in autoimmune diseases
such AGS and SLE with no curative therapies.
We developed an HTS-compatible cGAS enzymatic assay and used it to screen a 100k diversity library
resulting in the identification of four novel cGAS inhibitor chemotypes. Following the primary screen, we
performed iterative rounds of SAR informed by computational modeling and medicinal chemistry
expertise to prioritize two chemotypes with different mechanisms of action, and to increase potency into the
nanomolar range. During the course of this work we uncovered interplay between cGAS sensivity to
activation by nucleic acids and its modulation by small molecules that could inform the development of drugs
with a favorable therapeutic window. The goals of this Phase I proposal are to use structure-based design to
improve the potency and ADME/PK properties of the lead chemotypes and to demonstrate target engagement
and efficacy in cells. We have made substantial progress toward these goals, including generation of a high
resolution co-crystal X-ray structure for one of the lead chemotypes and demonstration of specific inhibition
of cGAS-driven IFN gene expression in human monocytes. In Phase I, we will continue to improve the
potency and other drug like properties of the two lead chemotypes using structure-based design enabled
by a more powerful computational method. In addition, we will use stem cell-derived neural cell models
and primary human peripheral immune cells to test inhibitor efficacy in a disease-relevant context.
Successful completion of these aims will clearly establish feasibility for Phase II in vivo efficacy
studies in a mouse model for AGS, a key milestone for clinical translation. Blocking cGAS with a small
molecule could lead to a curative therapy for AGS and would likely spur development of other drugs targeting
the cGAS/STING pathway with potential impact on millions of people suffering from debilitating autoimmune
diseases.
This is a multidisciplinary lead discovery effort that will combine BellBrook's extensive enzymology and
screening expertise, medicinal chemistry and translational research expertise from David Maloney and Matt
Boxer of Nexus Discovery Advisors (Frederick, MD - LOS and bios attached), structural
and biophysical expertise from XTAL BioStructures (Natick, MA, LOS attached) and
computational chemistry expertise from SilcsBio (Baltimore, MD – LOS attached). Dr. Keith Elkon, Co-
director of the Center for Innate Immunity and Immune Disease and Head of Rheumatology at University
of Washington School of Medicine is serving as a consultant (LOS and bio attached).
Under a separate SBIR grant (R44GM123833) in collaboration with Dr. Elkon, BellBrook is developing methods
for detecting cGAMP in cell and tissue samples to enable monitoring of cGAS inhibition in animal models, and
eventually for stratification and monitoring of patients in clinical studies; e.g., AGS patients or SLE patients with
high levels of cGAMP in PBMCs as candidates for cGAS inhibitors. The availability of a companion diagnostic
would increase the potential medical impact and value of a cGAS inhibitor drug substantially.
