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Jun 15, 2011 (Vol. 31, No. 12)

Small Molecule Simplicity Gives Them Staying Power

Chemical Entities Boast Some Distinct Advantages over Biological Entities

  • 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.

  • Targeting PIM Kinases

    The compounds were evaluated for their antitumor effects, but these were found to be modest. Since PIM is not a primary oncogene, Array investigators turned their attention to the anti-inflammatory potential of the compounds.

    The Array team then focused on T cells, and found that their panel of compounds exerted an antiproliferative effect. They further observed that in T cells, compounds that inhibit PIM 1/3 cause a decrease in Th17 mediated cytokine production, as well as inhibit proliferation of CD4+ T cells.

    Moreover, in a mouse experimental autoimmune encephalomyelitis model, AR460770 successfully inhibits ataxia and subdues relapses; only 1 out of 15 animals suffered relapse when treated continuously. “In certain settings, PIM 1/3 inhibitors differentiate from JAK inhibitors, but the clinical consequences of these observations will have to be worked out in patient trials,” Dr. Robinson stated.

    When evaluated in a mouse lupus model, the same compound negated proteinuria, which is a hallmark of the condition, and showed a marked reduction in kidney damage when histopathology studies were evaluated. In a similar vein, in a mouse inflammatory bowel disease model, treatment with the PIM inhibitor AR472317 showed efficacy equivalent to the anti-Il-12p40 antibody.

    “While there appears to be a relationship between the oncological and autoimmune effects of the PIM system, we don’t know exactly the key that ties them together, and this will have to be worked out through future investigations.”

  • S1P1R Agonists

    Click Image To Enlarge +
    Arena Pharmaceuticals is focused on discovering, developing, and commercializing drugs that target GPCRs in four major therapeutic areas: cardiovascular, central nervous system, inflammatory, and metabolic diseases.

    Robert M. Jones, Ph.D., senior director of medicinal chemistry at Arena Pharmaceuticals, and his colleagues are investigating agonists of the sphingosine-1-phosphate receptor (S1P1R) as a treatment for multiple sclerosis.

    Multiple sclerosis is characterized by the activation of autoimmune lymphocytes in the periphery; they mature and proliferate in the lymphatic system and then pass into the blood and cross the blood brain barrier where they cause inflammation, demyelination, and axonal damage. For decades the etiology of this condition has been in doubt.

    The S1P1R agonists activate and internalize the receptor, thereby blocking the sphingosine phosphate-dependent migration of activated T cells from the lymph nodes to efferent organs. This mechanism results in a decline in the level of T cells in the brain and leads to a decrease in the levels of cytokine markers such as IL-17 and IL-22, as well as a dampening of the inflammation within the brain.

    Dr. Jones and his colleagues have generated a series of modified molecules, starting with in-house screening hits. Moving through several iterations, they eventually arrived at the compound APD334.

    This molecule has been evaluated against a mouse model of experimental autoimmune encephalitis. It showed a powerful prophylactic effect in preventing the disease in animals receiving increasing doses of the drug, and was also effective in the therapeutic mode after the disease had been induced. Moreover it prevented the infiltration of T lymphocytes into the brain, suggesting it may be useful for the treatment of MS.

    In recent years, antibodies have been the area of pharmaceutical research that has generated the most excitement. Though small molecule agents have foundered in recent years, they have retained significant advantages over biological entities in terms of storage, delivery, and specificity.

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