New Kinase Inhibitors for the Treatment of Chronic Hematological Neoplasms-Editorial

Abstract

Protein kinases (PKs) and lipid kinases (LKs) are good targets for signal transduction therapy, as these enzymes are involved in signaling pathways, and are often related to the pathogenesis of myeloid and lymphoid malignancies. The attractiveness of PKs and LKs as druggable targets is enhanced by the fact that they are enzymes whose biological activity can be turned off by drugs that block their catalytic site. In the last few years, small molecular kinase inhibitors (KIs) have been synthesized and become available for preclinical studies and clinical trials. At present, thirteen kinase inhibitors have been approved in the United States, all for oncological indications. The first KI, introduced into clinical practice in 1998, was the tyrosine kinase inhibitor (TKI) imatinib mesylate, which became the first choice drug in chronic myeloid leukemia (CML) [1,2]. Subsequently, the secondgeneration TKIs, dasatinib and nilotinib, have been successfully used in the treatment of patients with CML, especially in cases refractory to imatinib [3,4]. Dasatinib and nilotinib have shown promising results in imatinib-resistant or intolerant CML patients, but they are not active against CML clones with a highly resistant T315I mutation [5]. Bosutinib is a third-generation TKI which has been studied in a first line setting in patients with CML and the results look very promising [6]. Nilotinib, dasatinib and bosutinib demonstrate increased potency over imatinib and inhibit most imatinib-resistant mutants, except T315I [7,8]. Despite very good results of current CML treatment, there is still room for improvement. In the last few years, several drugs with an inhibitory action towards the Aurora kinase family have been developed. Currently, a number of Aurora kinase inhibitors with different isoform selectivities are being evaluated in the clinic. The first Aurora kinase inhibitor to enter clinical trials is tozasertib (MK-0457, VX-680) [9]. This molecule inhibits multiple kinases, including Flt-3, and potently inhibits Abl and the T315I mutant [10,11]. Danusertib (PHA-739358) is another inhibitor of Bcr-Abl and Aurora kinases. In a Phase I clinical trial, a response occurred in 6 of 14 subjects with CML and Ph+ ALL [12]. The other Aurora kinase inhibitors with known activity against wild-type and mutated BCR-ABL are XL228 and AT9283. Both compounds have shown activity in CML patients in phase I clinical trials [13,14]. primary MF (PMF), post-polycythemia vera (PV) myelofibrosis, and post- essential thrombocythemia (ET) myelofibrosis. Ruxolitinib is currently undergoing evaluation in a Phase II clinical trial in patients with MF in combination with lenalidomide (ClinicalTrials.gov Identifier: NCT01375140) and in a Phase I clinical trial in combination with panobinostat (ClinicalTrials.gov Identifier: NCT01433445). SAR302503 (TG101348) is another JAK2-selective inhibitor created by structure-based drug design. This compound has been found to be a potent inhibitor of JAK2V617F and MPLW515L/K mutations commonly associated with PV and primary MF [17]. A reduction in palpable spleen size of more than 50% has been observed in 39% and 47% of patients after 6 and 12 cycles of therapy, respectively [18]. SAR302503 improved constitutional symptoms like fatigue, night sweats, pruritus and cough. Moreover, drug administration resulted in a significant decrease in the JAK2 V617F allele burden after 6 and 12 cycles of treatment, which is quite a unique ability among small molecule inhibitors of the JAK-STAT pathway. SAR302503 is currently recruiting for a Phase III multicenter, randomized study in patients with primary MF, post-PV MF, or post-ET MF with splenomegaly (JAKARTA study; ClinicalTrials.gov Identifier: NCT01437787).