Dual Kinase Targeting in Leukemia

Abstract

Pharmacological cancer therapy is often based on the concurrent inhibition of different survival pathways to improve treatment outcomes and to reduce the risk of relapses. While this strategy is traditionally pursued only through the co-administration of several drugs, the recent development of multi-targeting drugs (i.e., compounds intrinsically able to simultaneously target several macromolecules involved in cancer onset) has had a dramatic impact on cancer treatment. This review focuses on the most recent developments in dual-kinase inhibitors used in acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), and lymphoid tumors, giving details on preclinical studies as well as ongoing clinical trials. A brief overview of dual-targeting inhibitors (kinase/histone deacetylase (HDAC) and kinase/tubulin polymerization inhibitors) applied to leukemia is also given. Finally, the very recently developed Proteolysis Targeting Chimeras (PROTAC)-based kinase inhibitors are presented.

Discovery of a benzimidazole-based dual FLT3/TrKA inhibitor targeting acute myeloid leukemia

“…One approach to target AML heterogeneity and acquired resistance is the development of dual kinase inhibitors which might affect different oncogenic pathways related to AML or inhibit alternate signaling pathways that mediate resistance 38,39 . Of these, the previously mentioned midostaurin is a dual FLT3/SYK inhibitor, lestaurtinib is a dual FLT3/TrKA inhibitor, tandutinib and crenolanib are dual FLT3/PDGFR inhibitors, and gilteritinib is a dual FLT3/AXL inhibitor 40 .…”

Protein Kinases in Leukemias

“…The development of PK inhibitors in the treatment of hematologic malignancies such as leukemia emerged with imatinib in CML 20 years ago. Over the last two decades, many improvements have been made to introduce new pharmacological inhibitors in CML, CLL and AML [ 5 , 8 , 9 , 10 ]. This is illustrated by the seven reviews of this Special Issue, with a panel of the different mechanisms and signaling pathways involved in the response or resistance to these treatments.…”

“…We will also see that many other PK can be targeted jointly or sequentially to avoid the emergence of resistance or increase the therapeutic potential of the treatments. We can then use combinations or multi-target inhibitors to increase [ 1 , 4 , 8 ].…”

“…Second, if the molecules used in combination show synergy, they can then be used with efficacy at lower doses, which means lower secondary effects for patients. Finally, considering the heterogeneity of leukemia samples, combination therapy is more likely to benefit to large number of patients than single therapy with PK inhibitors [ 1 , 8 , 12 ].…”