STM Platform » GPM Pharmaceutical Development

G-protein mediated inflammation is a root cause or consequence of most aging and disease processes. Signum’s strategy is to develop GPMs to treat inflammatory skin disorders by restoring signaling imbalances in the cell. Given Arazine’s™ safety, its effectiveness as an anti-inflammatory and reduced immune-based inflammation effects in mice, 2nd generation analogs are attractive pharmaceutical development candidates. Efficacies of GPMs are broad in their anti-inflammatory spectrum, and since they target signal transduction pathways common to all inflammatory cells, we expect GPMs to be effective in a broad array of conditions involving dermal irritation and inflammation. Skin diseases of immediate interest are: rosacea, psoriasis, and eczema. Furthermore, since the effects of GPMs are locally restricted, this new class of anti-inflammatories are attractive candidates for treating respiratory disease.

Rosacea
Rosacea is a chronic, inflammatory skin disorder that affects an estimated 18 million Americans. The condition is characterized by a constellation of symptoms that include central facial erythema, telangiectasias, papules, granulomatous nodules, phyma formation and ocular changes. The central area of the face is most often affected, and the disease adopts a relapsing/remitting and sometimes progressive course. Four primary subtypes of rosacea have been recognized based on clinical appearance:

• Type 1: erythematotelangiectatic
• Type 2: papulopustular
• Type 3: phymatous
• Type 4: ocular

While research has not completely ruled out a microbial component in the pathogenesis of rosacea (e.g., Demodex mite overgrowth), there is strong evidence that rosacea is primarily an inflammatory disease. This view is supported by histopathologic findings that include follicular and perivascular leukocytic infiltrates (Feldman et al 2001, Powell et al 2005) and an absence of pathologic microflora. (Wilkin et al 2004) It is further reinforced by research demonstrating that the antibiotics effective against rosacea work by suppressing a variety of proinflammatory mediators thought to play a primary role in rosacea pathophysiology (Figure 1). (Dahl et al 2001) These include tumor necrosis factor alpha (TNF-α), the interleukins IL-1 and IL-6, and the neutrophil-derived compounds nitric oxide (NO), matrix metalloproteinases (MMPs), and various reactive oxygen species (ROS).

The most common topical treatment options include antimicrobial agents (e.g. Metrogel®, Clindamycin, Clindamycin-Benzoyl peroxide, Sodium Sulfacetamide/Sulfur and Finacea®) which inhibit ROS generation (highlighted yellow in Figure 1) by neutrophils, thereby reducing inflammation. However, these treatments do not reduce the initiating inflammatory events (inflammatory mediator release and neutrophil recruitment) of rosacea. Conversely, GPMs inhibit inflammation directly (highlighted in orange) and indirectly (highlighted in grey) by reducing activity and/or expression of all the key players in rosacea, not just ROS production (See Figure 2). Results demonstrate that GPMs:

• Inhibit release of key inflammatory mediators (e.g. TNF-α, IL-6, IL-8, VCAM-1, GM-CSF, Gro-α, MCP-1)
• Inhibit neutrophil adhesion and infiltration
• Inhibit ROS production from neutrophils

Given Arazine’s™ safety and effectiveness as an anti-inflammatory, second generation GPM compounds, provide an effective nonsteroidal alternative for patients suffering from skin diseases such as: rosacea, acne, psoriasis and eczema.

Respiratory Disease
Asthma is a chronic condition involving the respiratory system in which the airway constricts and becomes inflamed, often in response to one or more triggers. Chronic obstructive pulmonary disease (COPD) is a group of respiratory pathologies (emphysema, chronic bronchitis, and small airways disease) characterized by airflow that is not fully reversible. Both asthma and COPD are characterized by abnormal inflammatory response to noxious particles as well as airway hyper reactivity. The undesirable side effects of corticosteroids, which are the only effective inhaled anti-inflammatory compounds, suggest a significant possible opportunity for inhaled second-generation Arazine™ compounds. Currently, we are collaborating with the University of Pennsylvania to assess the effects of GPM compounds on airway inflammation.

Parkinson’s Disease
The nervous system, like the immune system, is highly dependent on cell-to-cell communication and research suggests that neuronal activity can be substantially influenced by the systemic application of Arazine™ and its derivatives. Results in experiments conducted by a group at Florida A & M University (FAMU) have indicated that these types of agents could be used to block Parkinson-like tremors in rats (link to abstract). Signum has established a collaborative effort with FAMU to develop specific second generation Arazine™ compounds that are optimized for the treatment of Parkinson’s. Also, we are currently developing PPMs that may also be effective in treating this disease.