When Gleevec hit the market in 2001 for chronic myelogenous leukemia , it was hailed as a major breakthrough in cancer treatment. Gleevec, which inhibits bcr-abl kinase, was the harbinger of targeted chemotherapy and represented a departure from the cytotoxics which, although effective, possess a broad array of adverse effects. A History of STI 571, written by Brian Druker, M.D., the principal investigator who championed the compound, not only illustrates the genesis of the drug itself but also the interdisciplinary teamwork required for drug discovery. Behind Gleevec came Iressa, Astra-Zeneca’s EGFR (a receptor tyrosine kinase) inhibitor.
Among the attractions of drugs like Gleevec and Iressa is their specificity toward a defined protein target which in theory should decrease toxicity from off target interactions. Because many pre-clinical compounds interact with the ATP binding region of the protein kinase active site, there is spillover to non-target kinases, but a surprising degree of specificity can be engineered into the molecules. This specificity may wind up being more critical for protein kinases validated as targets for inflammation as opposed to cancer in which some degree of toxicity may be more acceptable in the clinic.
Most drug tox results from off-target effects, i.e., some other protein is inhibited by the compound. Quite a number of drugs exhibit cardiotoxicity by blocking of the hERG ion channel. Screening compounds for hERG activity is common practice in the drug discovery biz. Gleevec passed this hurdle. Sometime a drug’s adverse effects only become apparent after more patients are exposed to the med. As reported in Monday’s the New York Times on Monday (7/24; see Warning Issued on Drug for Leukemia), some patients on Gleevec suffer serious heart damage. In this case, the adverse effect is not due to off target liabilities such as hERG antagonism, but instead it is mechanism based.
The original study is reported in Kerkela et al.’s paper, “Cardiotoxocity of the cancer therapeutic agent imatinib mesylate” which appears as an advance of print online publication in Nature Medicine. It’s nicely executed, and parses the connections between in vitro mechanism to in vivo effects. The swapping in of the imatinib resistant c-Abl domain, which then allowed cell survival in the presence of imantinib, is a pretty nifty bit. As an aside, this is something I love to see as part of target validation…stick in a mutant analog of target protein and examine the results of cell phenotype; siRNA just ain’t enough.
Here’s the abstract of the Nature Medicine paper:
Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.
Gleevec remains a breakthrough drug, and the principal investigator for the imatinib induced cardiotox study says as much:
“Gleevec is a wonderful drug, and patients with these diseases need to be on it,” Thomas Force, who led the study, said in a statement.
The results give a heads up to clinicians using Gleevec as part of their pharmacopoeia and for emerging drugs which target Abl and other non-receptor kinases.
It just goes to show that in the world of new drugs, to quote Roseanne Roseannadanna: “It’s always something.” For protein kinase targets, the imatinib results emphasize the need to understand (as much as can be) the signaling pathways in which a target kinase is entwined.
For a good overview of Gleevec’s arrival on the scene and the potential for protein kinase inhibitors as drugs, check out Approval heralds new generation of kinase inhibitors? from Nature Biotechnology (2001).