cancers Review Dual Kinase Targeting in Leukemia Luca Mologni 1, Giovanni Marzaro 2 , Sara Redaelli 1 and Alfonso Zambon 3,* 1 Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; [email protected] (L.M.); [email protected] (S.R.) 2 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, I-35131 Padova, Italy; [email protected] 3 Department of Chemistry and Geological Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy * Correspondence: [email protected]; Tel.: +39-059-2058-640 Simple Summary: A new option to treat cancer is based on the use of so-called multi-targeting drugs. This strategy can replace the standard treatment based on the co-administration of several drugs. An increased and uncontrolled activity of kinases (enzymes devoted to the regulation of several cell pathways) is often seen in hematological malignancies. The development of multi-kinase inhibitors is having a great impact on the treatment of this kind of cancer. Here, we review the most recent findings on this novel class of drugs. 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 (ki- nase/histone deacetylase (HDAC) and kinase/tubulin polymerization inhibitors) applied to leukemia Citation: Mologni, L.; Marzaro, G.; is also given. Finally, the very recently developed Proteolysis Targeting Chimeras (PROTAC)-based Redaelli, S.; Zambon, A. Dual Kinase kinase inhibitors are presented. Targeting in Leukemia. Cancers 2021, 13, 119. https://doi.org/10.3390/ Keywords: multi-kinase inhibitors; AML; CML; lymphoma; PROTAC cancers13010119 Received: 28 November 2020 Accepted: 28 December 2020 1. Introduction Published: 1 January 2021 One of the most spectacular breakthroughs in cancer therapy in the past 20 years is undoubtedly represented by the introduction of imatinib mesylate for the treatment of Publisher’s Note: MDPI stays neu- Philadelphia-positive (Ph+) leukemia [1,2]. The success of imatinib instilled the idea that tral with regard to jurisdictional clai- most tumors could be treated by a single, targeted drug that inhibits the main driver of ms in published maps and institutio- transformation. However, the initial enthusiasm subsided when it became clear that, on nal affiliations. the contrary, most tumors harbor at least two or more driver lesions, all of which need to be targeted to achieve disease control [3]. Even when one major driver can be identified, cells can often switch to alternative signaling to resist therapy [4] (Figure1). Therefore, Copyright: © 2021 by the authors. Li- dual targeting is being intensively investigated to improve treatment outcomes [5–7]. The censee MDPI, Basel, Switzerland. rationale behind the better anticancer activity of combined inhibition is based on (i) com- This article is an open access article plete and simultaneous suppression of cooperating oncogenic signals and (ii) concurrent distributed under the terms and con- block of bypass signaling tracks that may mediate drug resistance. Obviously, inhibiting ditions of the Creative Commons At- only one of two cooperating oncogenic signals will produce a partial effect. Moreover, a tribution (CC BY) license (https:// cancer cell is less likely to develop resistance to two drugs than to one (probability of dual creativecommons.org/licenses/by/ resistance is the product of the probabilities of single resistance). In this scenario, dually 4.0/). Cancers 2021, 13, 119. https://doi.org/10.3390/cancers13010119 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 26 Cancers 2021, 13, 119 2 of 26 this scenario, dually targeted molecules represent a further step: They achieve combined targetingtargeted moleculeswithout the represent unwanted a further combination step: They of achieve side effects combined that targetingcan be observed without thein traditionalunwanted dual combination targeting of by side two effects different that molecules. can be observed From a in medicinal traditional chemistry dual targeting point ofby view, two different“dual” may molecules. have different From ameanings: medicinal researchers chemistry pointcan develop of view, a “dual”dual inhibitor may have by intentionallydifferent meanings: aiming researchers at two specific can developtargets or a dualsimply inhibitor by exploiting by intentionally off-target aiming activity at of two a compoundspecific targets primarily or simply targeted by exploiting to another off-target kinase. activity As drugs of aare compound most often primarily not mono-spe- targeted cific,to another off-targets kinase. can As be drugs detrimental, are most oftenbeneficial, not mono-specific, or irrelevant off-targetsto the disease can be under detrimental, study. Thus,beneficial, in general, or irrelevant “dual” toindicates the disease a drug under that study.targets Thus,two relevant in general, kinases “dual” at comparable indicates a potency,drug that showing targets twosome relevant selectivity kinases over atother comparable unwanted potency, targets. showing This review some provides selectivity an overviewover other of unwanted the development targets. of This dual review inhibitors provides of kinase an overview targets for of the the treatment development of leu- of kemia.dual inhibitors of kinase targets for the treatment of leukemia. FigureFigure 1. 1. SignalingSignaling networks networks described described in in this this review review.. Cross-talks Cross-talks are indicated by blue arrows. 1.1.1.1. Dual Dual Kinase Kinase Targeting Targeting in AML AcuteAcute myeloid leukemia (AML)(AML) isis a a cancer cancer defined defined by by the the infiltration infiltration of boneof bone marrow, mar- row,blood, blood, and otherand other tissues tissues by proliferative, by proliferative, clonal, clonal, abnormally abnormally differentiated differentiated and poorly and poorlydifferentiated differentiated cells of cells the hematopoieticof the hematopoietic system system [8]. AML [8]. isAML characterized is characterized by cytogenetic by cyto- geneticand molecular and molecular heterogeneity; heterogeneity; genetic genetic abnormalities abnormalities include include amplifications, amplifications, deletions, dele- re- tions,arrangements, rearrangements, and point and mutations point mutations [8,9]. The [8,9]. last The WHO last classification WHO classification has added has RUNX1 added RUNX1mutations mutations and BCR-ABL1 and BCR-ABL1 rearrangements rearrangements to the previous to the previous main molecular main molecular markers (NPM1, mark- ersCEBPA, (NPM1, and CEBPA, FLT3) [10 and]. Most FLT3) AML [10]. patients Most AML respond patients well torespond chemotherapy, well to chemotherapy, but subsequent butrelapse subsequent is common, relapse and theis co prognosismmon, and is still the poor, prognosis with approximately is still poor, 30%with of approximately adult patients 30%under of 60adult years patients of age under achieving 60 years 5-year of survivalage achieving and a 5-year median survival survival and of 5a tomedian 10 months sur- vivalfor older of 5 patientsto 10 months [11–13 for]. older patients [11–13]. New,New, more targeted therapeutic approaches ha haveve been attempted to meet this clinical clinical need,need, such such as as the the use use of of fms-like fms-like tyrosine tyrosine kinase kinase 3 3 (FLT3) (FLT3) inhibitor midostaurin midostaurin [14,15], [14,15], isocitrateisocitrate dehydrogenase-2dehydrogenase-2 (IDH2)(IDH2) inhibitor inhibitor enasidenib enasidenib [16 [16],], and and calicheamicin calicheamicin conjugated conju- gatedanti-CD33-antibody anti-CD33-antibody gemtuzumab gemtuzumab [17]. [17]. As commonly As commonly observed, observed, the the major major limitation limitation of oftargeting targeting these these individual individual oncogenes oncogenes is is the the development development ofof resistance;resistance; hence, long-term remissionsremissions in in AML AML still still require require the the combined combined use use of ofcytotoxic cytotoxic chemotherapy chemotherapy and/or and/or tar- getedtargeted agents agents along along with with stem stem cell celltransplant, transplant, with with ensuing ensuing systemic systemic toxicity toxicity [11]. The [11]. dual The inhibitiondual inhibition of protein of protein kinases kinases in AML in AML has been has been extensively extensively explored explored to achieve to achieve response response to relapsingto relapsing and and resistant resistant tumors tumors avoiding avoiding toxic toxic side side effects, effects, mainly mainly involving involving co-inhibition co-inhibition ofof the the phosphatidylinositol 3-kinase(PI3K)/protein kinase kinase B (AKT)/mechanistic target target of rapamycinrapamycin (mTOR) (mTOR) (PI3K/AKT/mTOR) (PI3K/AKT/mTOR) pathway pathway and and FLT3 FLT3