ONCOLOGY: ENPP1
Our potential ENPP1 inhibitors target a key immune evasion mechanism
The immune system detects and attacks cancer through several pathways, including a signaling molecule called cGAMP. When cancer cells are damaged or dying, they release cGAMP, which activates the STING pathway. This triggers an innate immune response that transforms “cold” tumors “hot,” recruiting and activating T cells that then attack the tumor. However, turmos can utilize an enzyme called ENPP1 to degrade cGAMP, effectively silencing this alarm signal and evading detection. Elevated ENPP1 expression is linked to worse clinical outcomes, including shorter disease-free survival and increased metastases. This pattern is observed across several major cancers including colon (6%), lung (5%), pancreas (5%), and breast (4%). Because ENPP1 is a dominant mechanism for cGAMP degradation, it represents a uniquely attractive checkpoint for restoring the body’s natural immune response.
Because high ENPP1 inhibits the immune system, ENPP1 inhibition could spur immune activation
Highly potent, boron-based ENPP1 inhibitors may drive robust immune activation
Preclinical highlights
Single-agent efficacy comparable to PD-1 checkpoint inhibitors (multiple tumor models).
Synergistic effects when combined with anti-CTLA-4 (complete response rate was tripled in a colorectal cancer model).
Durable tumor regression and lasting immune memory (demonstrated resistance to tumor re-challenge in preclinical models).
Our boron-based ENPP1 inhibitors, including AN2-503321, are designed to act as phosphate mimetics that bind to metal ions in the ENPP1 active site with high potency and excellent drug-like properties. While this site has historically been challenging for small-molecule inhibitors, boron’s unique ability to mimic phosphate groups provides a distinct binding advantage. Beyond superior binding, our chemistry supports oral bioavailability and establishes a strong intellectual property positioning in a competitive target space.