Kill the Chaperone
Many cancers are the result of constitutively active JAK-STAT signaling, and attempts to control that pathway are proceeding apace. Incyte’s JAK inhibitor, ruxolitinib, is under fast-track review by the FDA, and other compounds are currently in clinical trials. These ATP-competitive inhibitors target the protein’s kinase activity.
“But, oftentimes, these kinases will mutate and no longer be responsive to their inhibitor,” said David Proia, Ph.D., senior scientist at Synta Pharmaceuticals.
The Boston-based company uses a different strategy to target JAK. Ganetespib is an inhibitor of Hsp90, a chaperone protein essential for the folding of hundreds of client proteins including JAK2. By inhibiting the activity of Hsp90, JAK2 is unable to adapt its active conformation and is subsequently targeted for degradation by the proteasome.
“Regardless of the mutations that develop in a client kinase like JAK they still require Hsp90 for their maturation, and so they’re still candidates of Hsp90 inhibitors,” Dr. Proia pointed out.
Leukemic cell lines driven by JAK2 mutations are highly sensitive to ganetespib, due in part to the degradation of JAK2 and subsequent inhibition of its substrates, STAT3 and STAT5, transcription factors linked to tumor cell survival, proliferation, and metastasis.
Yet, it is its effect on Hsp90’s other clients that intrigues Dr. Proia so much about ganetespib—most specifically the “overwhelming effect that Hsp90 inhibitors have on cell division and DNA replication. It’s the coordinated insult on kinases like JAK, AKT, as well as cyclins like CDC2 and other checkpoint proteins: the culmination of inhibition of those targets I think is what really gives such great potency to ganetespib.”
Despite this, ganetespib doesn’t seem to have the toxicity issues that earlier-generation Hsp90 inhibitors had. Over 400 cancer patients have been treated in the clinic so far—ganetespib is currently in Phase IIB/III trials—and it is generally well tolerated, according to Dr. Proia.