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.