July 28, 2014
These indoleamine 2,3-dioxygenase inhibitors may lead to drugs for cancer and other diseases. D. Boyall and co-inventors disclose compounds that act as indoleamine 2,3-dioxygenase (IDO) inhibitors and may be useful for treating or preventing a variety of diseases, disorders, or conditions including cancer and sepsis.
IDO is an enzyme that catalyzes the conversion of L-tryptophan (Trp, 1) to N-formylkynurenine (2) in the rate-limiting first step of Trp metabolism (see Figure 1). It is an inducible enzyme that has a primary role in immune cell modulation. Trp is an essential amino acid that is necessary for the biosynthesis of proteins, niacin, and serotonin. N-Formylkynurenine is a precursor for the biosynthesis of the immunomodulatory compound kynurenine and its derivatives.
The metabolic conversion of Trp to kynurenines may stop the growth of pathogens such as Toxoplasma gondii or Chlamydia trachomatis. It may also inhibit effector immune cells and promote adaptive immune suppression through by inducing and maintaining regulatory T cells. Increased metabolic conversion of Trp to kynurenines by IDO, however, has been linked to several immune system disorders such as infection, malignancy, autoimmune diseases, trauma, and AIDS.
Several studies provide evidence that link IDO activity to cancer. Some examples:
- Upregulation of IDO serves as a mechanism for tumor cells to escape immune surveillance.
- IDO is widely expressed in solid tumors and is found in primary and metastatic cancer cells.
- Proinflammatory cytokines, including type I and type II interferons, induce IDO activity in tumors.
- Increased infiltration of gastrointestinal tumors by effector T cells is accompanied by reduced IDO expression.
- IDO inhibitors reduce lymphocyte-dependent tumor growth.
- IDO inhibitors work synergistically with agents, such as irradiation, chemotherapy, and vaccines, that promote tumor antigenicity.
- IDO expression is found in antigen-presenting cells, including dendritic cells (DCs) that migrate to lymph nodes and induce anergy.
- IDO-positive DCs in tumor-draining lymph nodes (TDLNs) of cancer-bearing mice block T-cell activation by preventing the conversion of regulatory T cells to inflammatory T-helper–like cells. Inhibiting IDO activity allows this conversion to occur.
Taken together, this evidence indicates that inhibiting the IDO enzyme is a potential cancer therapy.
Other studies show that kynurenines can influence brain function. Kynurenine pathway metabolites may cause several harmful brain diseases. The fluctuations in their levels may lead to the occurrence of neurodegenerative diseases, schizophrenia, and depression. Vasodilation and shock associated with inflammation and sepsis may result from the production of kynurenine in blood vessels.
IDO activity is linked to dysregulated immune responses and impaired microvascular reactivity, as well as survival and disease severity in clinical studies on patients with sepsis and bacteremia. IDO activity correlates similarly with the progression of severe sepsis in patients who have community-acquired pneumonia. Thus, inhibiting IDO activity may provide treatments for bacterial infections and sepsis. In general, IDO Inhibition can maintain desired physiological Trp levels and suppress the expression of harmful levels of kynurenines.
The compounds of the invention have the general structure 3, shown in Figure 2. The inventors disclose 48 compounds of structure 3, including examples 4–9 in the same figure.
One of the biological assays used by the inventors was the cellular IDO1 inhibition assay. IC50 data classifications from this assay for the six examples are shown in the table. (IC50 is the half-maximal inhibitory concentration, or the concentration of an agent needed to reduce the activity of a biological process by 50%.)
|Example||Cellular IDO1 assay
|4||A||A: IC50 < 0.1 μΜ
B: IC50 = 0.1–1 μΜ
C: IC50 = 1–40 μΜ
(Vertex Pharmaceuticals [Cambridge, MA]. WIPO publication WO2014081689, May 30, 2014; Ahmed F. Abdel-Magid)