in a number of oncology clinical trials, which established the dose of 80 mg BID by mouth as recom- mended for hematologic malignancy trials. CEP 701 is being evaluated in patients with MF, PV and ET positive for JAK2V617F mutation. In the MF study 22 patients received CEP-701, most of whom (90%) were previously treated, presented with SU-11248  splenomegaly (90% of patients) with a median size from left costal margin of 19 cm, and with a median allele burden of 53%. 31 Eight patients (36%) were transfusion dependent at study entry. Median time on study was 4 months and responses were seen in 6 patients (27%) by International Working Group for Myelofibrosis Research and neuroscience Treatment (IWG-MRT) criteria.

All responses were defined as Clinical Improvement by IWG-MRT criteria and consisted of reduction in spleen size alone in 3 patients, transfusion independency in 2 patient entified, BCR-ABL inhibitors can be administered at doses that completely inhibit BCR-ABL and Elesclomol eliminate BCR-ABLositive cells without concerns for mechanism related adverse effects. In contrast, it is important to recognize that because of the localization of the V617F mutation in a region outside the ATP-binding pocket of JAK2 enzyme, ATP-competitive inhibitors of JAK2 kinase are not likely to distinguish between wild-type and mutant JAK2 enzymes. Therefore, JAK2 inhibitors, by virtue of their near equipotent activity on wild-type JAK2, which is important for normal hemato- poiesis, should have adverse myelosuppression as an expected side effect if administered at doses that aim to completely inhibit the mutant JAK2 enzyme. While they may prove to be effective at controlling hyperproliferation of hematopoietic cells in PV and ET, they may not be able to eliminate mutant clones in a manner similar to BCR-ABL inhibitors.

24 On the other hand, JAK inhibitors may have great therapeutic benefit by controlling the disease for patients with MPNs who suffer from debilitating signs (eg, splenomegaly) or constitutional symptoms that presumably result from high levels of circulating cytokines that signal through JAK enzymes. JAK2 Inhibitors in Clinical Development for MPNs A buy Bosutinib number of JAK2 inhibitors have been discovered and are currently being developed for MPNs. These early clinical trials are focused on patients with MF, among different MPNs, because of the serious unmet medical need of this condition. The life expectancy of patients with MF is shortened to about 5 to 7 years on average, and there is no approved therapy for this condition. Clinical studies are suitable for patients with MF with intermediate and high risk disease who need medical intervention to help them cope with advanced features of MF. The decision of whether to participate in a clinical study should be made between treating physicians and patients on a case by case basis, and it should include discussion about possible other forms of medical therapy (eg, hydroxyurea, thalidomide, or danazol), including bone marrow transplantation. While bone marrow transplantation is a therapeutic option that potentially may eliminate the disease and provide long-term disease-free survival for patients with MF, great majority of patients with MF are elderly and/or have medical comorbidities precluding transplant.

Four JAK2 inhibitors are in develop- 637 2  ment for which preliminary clinical findings are publicly available through publications or oral presentations. INCB018424 The JAK2 purchase Bosutinib inhibitor INCB018424 was the first to be evaluated in PMF and post-PV/ET MF; it entered clinical trials in mid-2007. INCB018424 (structure exemplified in PCT/US2008/066662; Figure 1 ) is a potent and selective inhibitor of JAK1 and JAK2 with IC 50 of 3.3 and 2.8 nM, respectively ( Table 1 ). It demonstrated modest selectivity against Tyk2 (~ 6-fold) and marked selectivity ( 130-fold) against JAK3. 25 No significant inhibition against a commer- cial panel of 26 additional kinases was observed when INCB018424 was tested at a concentration