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cGAS is an innate immune sensor of nucleic acids that, when aberrantly activated, leads to auto-inflammation and tissue damage. cGAS plays a key role in pro-inflammatory diseases such as lupus and dermatomyositis. With ReSOLVE™, we solved the high-resolution co-crystal structure of cGAS and developed a portfolio of high affinity inhibitors, including VENT-03. VENT-03 is a potent, selective, oral, small molecule cGAS inhibitor that, to our knowledge, is the first cGAS inhibitor to enter clinical development.

cGAS

The recognition of foreign nucleic acids inside the cell is a crucial element of the innate immune response. This is accomplished by pattern recognition receptors (PRRs), such as cyclic GMP–AMP synthase (cGAS). cGAS senses intracytoplasmic double-stranded DNA (dsDNA), triggering a cascade that involves the synthesis of the second messenger 2′,3′-cyclic GMP–AMP (cGAMP), which, in turn, binds to stimulator of interferon genes (STING), triggering pro-inflammatory gene expression that culminates with the activation of the Type I interferon and NF-κB pathways. As the binding of cGAS to dsDNA is independent of the nucleic acid sequence, both external (e.g., from pathogens) and internal (e.g., from the mitochondria) DNA lead to its activation. The cGAS pathway is implicated in numerous auto-inflammatory diseases.

Aberrant Accumulation of Cytoplasmic dsDNA
Aberrant Accumulation of cytoplasmic dsDNA - diagram
cGAS-STING Pathway Activation
cGAS-STING diagram
Inflammation
Inflammatory cytokines - diagram
Tissue Damage
Auto Inflammatory Disease - diagram

Aberrant activation of the cGAS pathway is implicated in a wide range of diseases

Type I interferonopathies are a family of inherited auto-inflammatory diseases, of which the majority are caused by mutations in genes involved in nucleic acid sensing and metabolism. Aicardi-Goutières Syndrome (AGS), the first monogenic interferonopathy identified, has been linked to aberrant accumulation of endogenous DNA and activation of the cGAS/STING pathway. Similarly, defective nucleic acid metabolism and cGAS activation have been linked to genetic forms of chilblain lupus and systemic lupus.

Given that the pathophysiology and presentation of these genetic diseases have significant similarities with idiopathic complex diseases such as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), systemic sclerosis (SSc), and dermatomyositis (DM), these diseases represent highly compelling opportunities for treatment with a cGAS inhibitor. cGAS is implicated in several neuroimmune and neurodegenerative conditions as well.

Validation of the cGAS pathway

Targeting Type I interferons for the treatment of SLE has been validated through the approval of anifrolumab, an anti-IFNAR antibody for the treatment of this disease. However, anifrolumab causes general suppression of all Type I interferon responses, not only those that are cGAS-mediated (DNA-sensing), but also responses driven by RNA-sensing and other triggers. Selectively targeting DNA-driven Type 1 interferon responses through the inhibition of the cGAS pathway has the potential to demonstrate efficacy and safety advantages. Furthermore, the cGAS pathway triggers a non-interferon-mediated inflammatory response that is important to immunological conditions and not addressed by currently approved medications.

ReSOLVE™ in action

Despite significant efforts in the industry over the past decade, no cGAS inhibitor has entered clinical development.

In 2020, following the founding of Ventus, we discovered that the published co-crystal structure of cGAS was incorrect. With our in-house structural biology capabilities, we generated accurate co-crystal structures of cGAS with proprietary inhibitors. This structural enablement led to the development of increasingly potent cGAS inhibitors, but, eventually, we hit the same potency plateau reported by others in the field.

Using ReSOLVE™, we found that the catalytic pocket of cGAS adopts many conformations. Importantly, we found that some of these conformations were significantly larger than those observed experimentally and contained substantial high energy solvation, offering new opportunities for ligand optimization. ReSOLVE™ enabled us to generate a detailed understanding of the solvation structure of the cGAS protein and to identify previously unknown conformations of the active site. These proprietary insights guided us to optimize compounds with information available only to Ventus and enabled the development of chemical matter with high potency and desirable pharmacological properties, leading to our portfolio of orally bioavailable small molecule cGAS inhibitors, including our lead cGAS program, VENT-03, as well as our systemic and brain-penetrant follow-on compounds.

Learn more about our platform.

VENT-03: A first-in-class oral small molecule inhibitor of cGAS

Phase 1 clinical trial ongoing

VENT-03, our inaugural development candidate in our cGAS franchise, is a potent and highly selective systemic cGAS inhibitor with outstanding pharmaceutical properties, including excellent intrinsic and cellular potency and predictable PK across multiple species. In preclinical studies, VENT-03 demonstrated robust and dose-dependent reduction of cGAMP and IFN-α in multiple disease-relevant models.

A Phase 1 clinical trial of VENT-03 is ongoing. The trial is designed to fully explore the pharmacodynamics, safety, and tolerability of VENT-03 across a broad range of single and multiple ascending doses.

Beyond VENT-03

In addition to VENT-03, we continue to generate increasingly potent compounds across multiple chemical series, including ones that are brain-penetrant. The role of the cGAS pathway is implicated in multiple neuroinflammatory diseases, including ALS, Parkinson’s disease, and traumatic brain injury. We are also developing a topical formulation given the high incidence of skin manifestations observed in many auto-inflammatory diseases.

cGAS-related publications

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