Macrolides as Anti-Inflammatories
Cempra Pharmaceuticals is investigating the anti-inflammatory properties of macrolide antibiotics conventionally employed as antibacterial agents. Prabhavathi Fernandes, Ph.D., CEO, discussed the search for macrolides with low activity as antibiotics and elevated performance in treating chronic inflammatory disease.
“The antibacterial effects can be differentiated from the anti-inflammatory effects, especially in late-stage chronic inflammatory disease. We have found that the erythromycin molecule is desirable as a chemical backbone because it concentrates in tissues including the lung, macrophages, and dermis.”
However, it has not been approved for long-term treatments due to its propensity to select for resistant bacterial strains. For this reason, the company is searching for alternative structures that display lower antibiotic activity and elevated anti-inflammatory properties.
The current model forming the theoretical framework for these investigations is based on oxidative stress triggering gene repression through the activation of PI3K, or phosphatidylinositol 3´ kinase, an enzyme known to play a critical role in tumorigenesis. When PI3K phosphorylates the histone deacetylase 2 (HDAC2), the enzyme is destroyed and an inflammation cascade takes place.
Based on these considerations, molecules that block PI3K should possess anti-inflammatory and antitumor activities. And indeed, in animal and in vitro models, the macrolides erythromycin, clarithromycin, and solithromycin demonstrated anti-inflammatory effects.
Currently, Cempra is pursuing two modified ketolide molecules, A3 and A6. “Our lead macrolides have little antibacterial activity and belong to a series with little CYP3A4 (a mixed function oxidase), hERG (a potassium ion channel), or motilin (housekeeper of the gut) inhibition.”
John Robinson, Ph.D., a research investigator at Array BioPharma, discussed the PIM kinase family, consisting of three serine/threonine kinases. The PIM genes are induced by STAT and function as a critical signaling node downstream of cytokine, growth factor, and oncogene pathways, thereby regulating a variety of cellular functions.
“We originally picked PIM as a possible entryway into antitumor agents because of its relationship to STAT, and the fact that many oncogenes are known to drive through STAT-3/5,” Dr. Robinson said.
Because of their pivotal regulatory function, Array BioPharma spent six to eight months creating a number of selective inhibitors with high solubility and permeability as well as oral bioavailability. One of these, AR460770, is a potent and selective PIM 1/3 inhibitor.