Pasithea Therapeutics Corp. has announced preclinical data demonstrating that its next-generation macrocyclic MEK inhibitor PAS-004 provides superior inhibition of ETS2-driven inflammatory responses compared to the FDA-approved MEK inhibitor selumetinib in a human macrophage model of chronic inflammation that mimics inflammatory bowel disease (IBD).
The study was conducted at the Francis Crick Institute in London by Dr. James Lee, a gastroenterologist and Clinician Scientist Group Leader at the Genetic Mechanisms of Disease Laboratory. Dr. Lee was the lead author of a landmark 2024 Nature paper that identified ETS2 as a master regulator of inflammatory responses in IBD and uncovered a novel genetic mechanism behind the disease.
Superior ETS2 Pathway Inhibition
Using RNA sequencing to measure gene expression, PAS-004 consistently outperformed selumetinib across all tested doses (0.01 μM, 0.1 μM, and 1 μM), showing greater downregulation of ETS2 target genes as well as experimentally validated MEK1/2 pathway genes. These data suggest more robust and durable MEK inhibition by PAS-004 under inflammatory conditions.
At all doses tested, PAS-004 demonstrated superior and stronger suppression of ETS2 signaling compared to selumetinib. The compound significantly reduced ETS2-dependent functions such as cytokine production, phagocytosis, and reactive oxygen species (ROS) generation, all known to be central to chronic inflammation.
Mechanistic Advantages
Gene Set Enrichment Analysis revealed that PAS-004's effects more closely mirrored ETS2 knockout profiles, with a higher normalized enrichment score (-3.96 vs -3.56) and greater statistical significance (1.2 x 10⁻²⁵⁰ vs 3.7 x 10⁻⁷⁴) compared to selumetinib.
"Collectively, these in vitro data suggest that, compared to selumetinib, PAS-004 is likely to provide superior inhibition of the macrophage inflammatory pathways orchestrated by ETS2," commented Dr. Lee. "Blocking single cytokines is a common strategy used to treat chronic inflammatory diseases, but growing evidence suggests that targeting several at once may be a better approach."
Broader Cytokine Targeting
Dr. Lee noted that blocking ETS2 signaling through MEK1/2 inhibition affects multiple cytokines, including TNFα and IL-23, which are individually targeted by existing therapies, and IL-1β, which has been implicated in treatment resistance and is not directly modulated by JAK inhibitors.
"JAK inhibitors have dominated the IBD oral treatment landscape over the last few years and we now have genetic evidence that MEK inhibition should affect a broader range of pathogenic cytokines including IL-1β, a critical cytokine that JAK inhibitors do not impact," commented Dr. Tiago Reis Marques, Chief Executive Officer of Pasithea.
Clinical Development Potential
Based on the low level of adverse events and tolerable safety data observed in Pasithea's ongoing Phase 1 clinical trial in advanced cancer patients, Dr. Marques believes PAS-004 has the potential to be a new oral treatment option for those suffering from inflammatory diseases such as IBD.
Dr. Larry Steinman, Executive Chairman of Pasithea, added, "I have studied inflammation and inflammatory pathways for over 50 years and today's results are exciting as we consider better drugs targeting inflammatory conditions. These preclinical results suggest PAS-004's ability to block ETS2 signaling and target multiple cytokines opens the potential for testing PAS-004 in large market inflammatory indications."
The findings position PAS-004 for potential expansion beyond MAPK pathway driven tumors into immune-mediated inflammatory diseases such as IBD and ankylosing spondylitis, representing a significant opportunity in large addressable market diseases.
