PDE4 Platform

Innovative Approach to Validated PDE4 Inhibitor for the Treatment of Immune, Inflammatory and Fibrotic Diseases

Our innovative approach targets Phosphodiesterase 4 (PDE4), a critical enzyme involved in regulating intracellular levels of cyclic adenosine monophosphate (cAMP). cAMP is a messenger molecule that plays a significant role in inflammation and immune response. By breaking down cAMP, PDE4 modulates signaling pathways that control the production of pro-inflammatory and anti-inflammatory molecules. This regulation is vital in maintaining the balance of immune and inflammatory responses in the body.

The Role of PDE4 in Immune Regulation

Regulation of cAMP Levels

PDE4 breaks down cyclic adenosine monophosphate (cAMP), a key signaling molecule in various cellular processes.

Modulation of Inflammatory Pathways

By controlling cAMP levels, PDE4 influences the signaling pathways that regulate the production of pro-inflammatory and anti-inflammatory molecules.

Immune Cell Function

PDE4 affects the activation and function of immune cells such as T cells, macrophages, and neutrophils, playing a crucial role in immune responses.

Chronic Inflammation

Elevated PDE4 activity is associated with increased production of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-17), leading to chronic inflammation in diseases like ulcerative colitis and other inflammatory conditions.

Fibrosis Development

PDE4 activity impacts the signaling pathways that regulate cell proliferation, differentiation, and extracellular matrix production, contributing to tissue scarring and organ dysfunction in fibrotic diseases.

Novel Oral PDE4 Prodrug Acts Locally at Site of Disease

Our innovative PDE4 inhibitor prodrug allows us to leverage a validated PDE4 target with potential to avoid systemic exposure and improve safety.

Key OTEZLA® (Apremilast) Stats

Systemically Active

Dose-limiting side effects include:

  • Nausea
  • Headache
  • Vomiting

TNF-Alpha at IC50 (key inflammatory marker): 0.41 μM

Our Novel Oral PDE4 Prodrug

Locally Delivered and Active Prodrug

Lack of systemic exposure potentially eliminates concerns for CNS adverse events

Improved therapeutic window enables maximal PDE4 inhibition supporting higher cAMP tissue levels

TNF-Alpha at IC50: 0.022 μM (~20x more potent)

PALI-2108

Precision Medicine Approach

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