Ompenaclid (RGX-202) is an oral small molecule inhibitor of SLC6A8 that induces apoptosis (cell death) of colorectal cancer cells.
Mechanism of Action
Creatine Kinase-B (CKB) was revealed as an RNA dysregulated cancer driver in KRAS mutant colorectal cancer (CRC) by the RNA-DRIVEr™ platform. CKB is activated in response to tumor hypoxia (low oxygen) to enable cancer cells to generate ATP and other nucleotides via phospho-creatine.
Phospho-creatine is imported into CKB expressing (CKB+) cancer cells via the creatine transporter SLC6A8. ompenaclid (RGX-202) is an oral first-in-class creatine mimetic NCE that acts as a competitive inhibitor of the creatine transporter SLC6A8.
In the setting of tumor hypoxia (which is a common feature of CRC) ompenaclid (RGX-202)-mediated depletion of phospho-creatine (P-Cr) impairs synthesis of ATP and other nucleotides that are required for colorectal cancer cell survival, resulting in potent induction of apoptosis (cancer cell death).
Since healthy (non-tumor) tissue is not hypoxic under normal conditions, inhibition of SLC6A8 by ompenaclid (RGX-202) largely leaves healthy tissue unaffected, providing a wide therapeutic window.
Ompenaclid (RGX-202) is currently being tested in combination with the standard-of-care regimen FOLFIRI and bevacizumab in a Phase 1b clinical trial for the 2nd line treatment of patients with advanced colorectal cancer whose tumors have a mutation in the RAS gene (~40-45% of colorectal cancers).
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