There is a profound association between cancer and inflammatory processes, according to Raffaella Sordella, Ph.D., assistant professor at Cold Spring Harbor Laboratory. Dr. Sordella was a keynote speaker at CHI’s recent conference on drug discovery chemistry.
Discussions at the meeting about small molecule approaches to anti-inflammatory therapies devoted considerable time to the link between malignancy and inflammation. Chronic inflammation not only predisposes individuals to cancer and correlates negatively with cancer prognosis, but inflammation may, in fact, hamper tumor response to drug treatment.
The Janus kinases, or JAKs, a family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals, are an important target for drugs directed against cancer and inflammatory processes. Incyte has developed a number of candidate compounds including INCB18424, according to James D. Rodgers, Ph.D., executive director of medicinal chemistry.
“Our rationale is based upon the observation that dysregulation of the JAK-STAT pathway is a hallmark of both chronic inflammatory diseases and myeloproliferative neoplasms,” Dr. Rodgers explained. “Indeed, a single amino acid mutation, V617F, in the JAK2 gene was recently identified in a variety of such conditions including polycythemia vera, essential thrombocythemia, and myelofibrosis.”
The mutant JAK2 leads to unchecked signaling through cytokine and growth factor receptors without the need for the ligands. This permits phosphorylation and activation of STATs (signal transducers and activators of transcription proteins). The activated STATs dissociate from the receptor and form dimers, then migrate to the cell nucleus where they regulate transcription of selected genes.
It is well known that transgenic mice that do not express JAK1 have defective responses to some cytokines such as IL-6 and interferon-gamma (IFN-γ). Although there are four members in the JAK family of kinases, the company focused on developing selective JAK1 and JAK2 inhibitors based on its understanding that IL-6, a clinically validated target in autoimmune diseases such as rheumatoid arthritis, signals through JAK1 and JAK2.
An additional piece of the puzzle is the observation that IL-6 is also involved in the pathogenesis of myeloproliferative neoplasms. With knowledge of JAK inhibitors originally developed by Merck and Pfizer, Dr. Rodgers and his colleagues have investigated a number of polycyclic molecules with respect to their inhibition spectrum, oral bioavailability, and pharmacokinetics.
“We designed a series of potent and selective JAK1 and JAK2 inhibitors which we studied in an IL-6 driven cell line,” Dr. Rodgers continued. After many rounds of discovery, evaluation, and elimination, the company selected the compound INCB018424. “We completed Phase III trials for the treatment of myelofibrosis, and we are on schedule to file a new drug application in the second quarter of 2011.”
The JAK pathway is also a validated therapeutic target for psoriasis and potentially other inflammatory cutaneous diseases.
Targeting IL-17 Release
Daniel Vitt, Ph.D., is CSO for R&D at 4SC, where he directs studies on IL-17, one of the key cytokines responsible for autoimmune dysfunction. The company has introduced vidofludimus, an orally available dual inhibitor of IL-17 A and F as well as dihydro-orotate dehydrogenase (DHODH), used in the treatment of rheumatoid arthritis and inflammatory bowel disease.
According to Dr. Vitt, the company is currently pursuing an inhibitor-optimization program including a family of molecules with sub nanomolar inhibitor activity. The goal of the program is to build a new systemic baseline therapy for the treatment of IL-17 associated autoimmune diseases including psoriasis, multiple sclerosis, and lupus erythematosis.
IL-17 is produced by subset of T cells known as T helper 17 cells (Th17), which play a role in autoimmune diseases. Dr. Vitt noted that they are upregulated in psoriatic tissue, and thus, the inhibition of IL-17 and IFNγ hold promise as a treatment for psoriasis. IL-17A, the founding member of the IL-17 family, is one of the key cytokines for driving and maintaining rheumatoid arthritis.
In clinical trials, Vidofludimus showed an 89% positive response rate in the treatment of inflammatory bowel disease, indicating a broad potential in ameliorating immune dysfunction.
In vitro studies demonstrate that it is active specifically against T-cell cytokines, inhibiting T and B cell proliferation and IL-17 A and F release. The suppression of the immune response is apparently through the inhibition of DHODH, an enzyme required for the synthesis of DNA and RNA. It is noteworthy that, while cell proliferation reestablishes itself after addition of uridine, IL-17 release appears to be permanently shut off.
Dr. Vitt and his colleagues are now investigating next-generation compounds with markedly improved activity over vidofludimus. One of these, SC89732, has been shown to shut down IL-17 A and F production as well as IFN-γ at low nanomolar concentrations, while having no effect on IL1-β in activated T cells.
A second candidate compound, SC92366, has been evaluated for in vitro cellular toxicity and specificity. It showed no cytotoxic effect on unstimulated peripheral B lymphocytes, nor any kinase-inhibiting effects.