cancers
`
`Review
`
`FDA-Approved Drugs for Hematological Malignancies—The
`Last Decade Review
`
`Aleksandra Sochacka-Cwikta *, Marcin Maczyriski © and Andrzej Regiec ®
`
`Department of Organic Chemistry and Drug Technology, Faculty of Pharmacy, Wroclaw Medical University,
`211A BorowskaStreet, 50-556 Wroclaw, Poland; marcin.maczynski@umw.edu.pl (M.M.);
`andrzej.regiec@umw.edu.pl (A.R.)
`* Correspondence: aleksandra.sochacka-cwikla@umw.edu.pl; Tel.: +48-7178-406-34
`
`Simple Summary: Hematological malignancies are diseases involving the abnormal production of
`bloodcells. The aim of the study is to collect comprehensive information on new drugs usedin the
`treatment of blood cancers which haveintroducedinto therapy in the last decade. The approved
`drugs were analyzed for their structures andtheir biological activity mechanisms.
`
`Abstract: Hematological malignancies, also referred to as blood cancers, are a group of diseases
`involving abnormalcell growth andpersisting in the blood, lymph nodes, or bone marrow. The
`developmentof new targeted therapies including small molecule inhibitors, monoclonal antibod-
`ies, bispecific T cell engagers, antibody-drug conjugates, recombinant immunotoxins, and, finally,
`Chimeric Antigen Receptor T (CAR-T)cells has improvedtheclinical outcomes for blood cancers.
`In this review, we summarized 52 drugs that were divided into small molecule and macromolecule
`agents, approved by the Food and Drug Administration (FDA)in the period between 2011 and 2021
`for the treatment of hematological malignancies. Forty of them have also been approved by the
`European Medicines Agency (EMA). We analyzed the FDA-approveddrugsby investigating both
`their structures and mechanismsof action. It should be emphasized that the numberof targeted
`drugs wassignificantly higher (46 drugs) than chemotherapy agents (6 drugs). We highlight recent
`advancesin the design of drugs that are used to treat hematological malignancies, which make them
`moreeffective andless toxic.
`
`Keywords: small molecule agents; macromolecule agents; hematological malignancies; FDA; EMA
`
`
`1. Introduction
`
`G checkfor
`updates
`Citation: Sochacka-Cwikia, A.;
`Maczynski, M.; Regiec, A.
`FDA-Approved Drugsfor
`Hematological Malignancies—The
`Last Decade Review. Cancers 2022, 14,
`87. https://doi.org/10.3390/
`cancers14010087
`
`Academic Editor: Marco Picardi
`
`Received: 1 November2021
`
`Accepted: 20 December 2021
`Published: 24 December2021
`
`Publisher’s Note: MDPIstays neutral
`with regard to jurisdictional claimsin
`published mapsandinstitutionalaffil-
`iations.
`
`Hematological malignancies, also known as blood cancers, are diseases characterized
`by the clonal proliferation of blood-forming cells, which occur in blood, bone marrow, or
`lymph nodes. Hematological malignancies include wild range types of leukemia, lym-
`phoma, and myeloma,classified into two types: lymphoid and myeloid [1]. According to
`its mechanism of action, the drugs used for the treatment of hematological malignancies can
`historically be divided into the following groups: deoxyribonucleic acid (DNA)-interactive
`agents, antimetabolites, anti-tubulin agents, and molecular targeting agents such as highly
`specific small molecules and monoclonal antibodies. DNA interactive agents, the old-
`est group of anticancer medications, can be primarily categorized into alkylating agents,
`cross-linking agents, intercalating agents, topoisomerase inhibitors, and DNA-cleaving
`agents [2]. The first alkylating agent approved by the Food and Drug Administration
`(FDA) was chlormethine (mechlorethamine), also called nitrogen mustard. Goodman
`and coworkers described, in 1946, the pharmacological effect of mechlorethamine on
`Hodgkin’s lymphoma, lymphosarcoma, and leukemia [3], which led to this drug being
`registered in 1949 [4]. As a result of work on folic acid antagonists carried out by Farber,
`the next class of drug was developed, i.e., antifolate. In 1948, Farber reported the use
`of aminopterin, which was the 4-amino derivative of folic acid, to treat children with
`CELGENE 2115
`APOTEX v. CELGENE
`IPR2023-00512
`
`Copyright: © 2021 by the authors.
`Licensee MDPI, Basel, Switzerland.
`This article is an open accessarticle
`distributed under
`the terms and
`conditions of the Creative Commons
`
`Attribution (CC BY) license (https://
`creativecommons.org/licenses/by/
`4.0/).
`
`Cancers 2022, 14, 87. https: / /doi.org/10.3390/cancers14010087
`
`https:/ /www.mdpi.com/journal/cancers
`
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`acute leukemia [5]. Methotrexate (amethopterin) replaced aminopterin in the treatment
`of patients in 1953 becauseit has a better therapy-versus-toxicity ratio [6,7]. Then, mer-
`captopurine and fluorouracil were discoveredasthe first structural analogs of purine and
`pyrimidine, respectively. Mercaptopurine was synthesized by Elionetal. in 1952 [8] and
`wasfirst FDA-approved in 1953 [9], while fluorouracil was developed by Dushinskyetal.
`in 1957 [10] and received first approval in 1962 [11]. These drugs were widely used for
`the treatment of both solid and hematological malignancies [12]. Generally, folate, purine,
`and pyrimidine antagonists form oneof the oldest classes of anticancer drugs, i.e., an-
`timetabolites. The next discovered agents for the treatment of hematological malignancies
`were natural plant alkaloids with anti-tubulin activity. Noble and Beerisolated twofirst
`vincaalkaloids,i.e., vinblastine and vincristine, from Catharanthus roseus (L.) G. Don [13].
`Both compoundsreceived extensive clinical evaluation leading to the FDA approvalof
`vincristine in 1963 as therapies for a variety of cancers [14]. Other natural products were
`cytotoxic antibiotics such as bleomycin and doxorubicin. Bleomycin was found in Strep-
`tomycesverticillus by Umezawaetal. in 1962. This antibiotic wasthe first DNA-cleaving
`agentto be registered, in 1973 [15], and can be used to treat malignant lymphomaas well
`as squamouscell carcinomaof the skin, head, and neck [16]. Doxorubicin wasisolated
`from Streptomyces peucetius var. caesius in 1967in Italy [17], and wasfirst FDA-approved in
`1974 [18]. The drug showed anticanceractivity via multiple mechanismsincluding interca-
`lation into DNAandinhibition of topoisomeraseII activity. Doxorubicin was commonly
`used for the treatmentof various hematological malignancies [19]. In 1965, Rosenberg and
`co-workersdiscoveredthat cisplatin, the platinum coordination complex synthesized by
`Peyronefor the first time in 1845 [20], caused inhibition of cellular division [21]. Then,
`cisplatin was entered in trials against a wide range of cancers where it showed potent
`anticancer activity through the cross-linking of DNA. The drug was approved by the
`FDAin 1978 and, since that time, has been usedasa first-line treatmentfor patients with
`leukemia or lymphomas. Currently, it is still one of the most successful anticancer agents
`usedin clinical practice [22]. A milestone for blood cancer treatment wasthe discovery of
`targeted therapy, consisting of the inhibition of molecular targets that are specific molecules
`involved in the growth, progression, and spread of cancer by monoclonal antibodies or
`small selective molecules. The first FDA-approved monoclonal antibody for the treatment
`of hematological malignancies, a genetically engineered chimeric anti-cluster of differentia-
`tion 20 (CD20) antibody, was rituximab. The drug wasregistered in 1997 for the treatment
`of relapsedorrefractory, B-cell, low-grade,or follicular non-Hodgkin’s lymphoma (LG/F
`NHL)[23]. Imatinib wasthefirst small molecule inhibitor (SMI) to be foundto be selective
`against variousprotein tyrosine kinases. It was synthesized by Buchdungerin 1996 and ap-
`proved by the FDA in 2001. The drug wasindicated for patients with chronic myelogenous
`leukemia (CML) [24].
`Thisarticle is an overview of drugs usedin the treatment of hematological malignan-
`cies, which was approved by the FDA from 2011 until 2021. The most recent examples of
`small molecule and macromolecule drugs are detailed, focusing on the initial approval
`date, chemical structure, molecular target, route of administration, indication, and the
`most commonadverseeffects for each agent. Depending on the mechanism ofaction, the
`approved drugsare assigned to two categories: chemotherapy andtargeted agents. In the
`presentreview, the medications containing a new molecular entity, or old active ingredient
`but in a new formulation, are summarized. The drugsreferred to as biosimilars are also
`included. The biosimilars are an important group of biologic medicines which, although
`similar in structure, purity, and function to their reference products, with no meaningful
`differencesin clinical efficacy and safety, increase access to hematologic malignancyther-
`apies by mitigating the treatment costs [25]. Notably, the drugs received supplemental
`indications in the period from 2011 to 2021 but were originally approved before 2011, and
`drugsusedto treat the side effects of cancer treatmentare not includedin this work.
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`2. Small Molecule Anticancer Drugs
`2.1. Various Protein Kinase Inhibitors as Anticancer Agents
`Protein kinases are enzymes, whichcatalyse the reversible phosphorylation of proteins.
`This reaction is one of the most important regulatory mechanismsandplaysa crucial role
`in processes suchasthe transduction of external signals andthecell cycle regulation. There-
`fore, protein kinases inhibitors are an important group in need of new drugs, especially
`anticancer drugs. Protein kinase inhibitors are divided into three types. Type I inhibitors
`bind within and aroundthe adenosinetriphosphate (ATP) bindingsite of a catalytically
`active protein kinase, causing inhibition of its phosphorylation. TypeII inhibitors bind to
`a hydrophobic pocket adjacent to the ATP binding site and are usually nonselective. In
`contrast, type III inhibitors bindto allosteric sites, remote from the ATP site, and are highly
`selective [26].
`
`2.1.1. Tyrosine Kinase (TK) Inhibitors
`Tyrosine kinases (TKs) are enzymesthat selectively phosphorylate the hydroxyl groups
`of a tyrosine residue in different proteins using ATP. They havea sharein the regulation of
`most fundamental cellular processes such as growth,differentiation, proliferation, survival,
`migration, and the metabolism ofcells, as well as programmedcell death in response to
`extracellular and intracellular stimuli [27]. The human genomecontainsat least 90 tyrosine
`kinase genes, which codify 58 receptor tyrosine kinases (RTKs) and 32 nonreceptor tyrosine
`kinases (NRTKs) [28]. RTKs are surface transmembrane receptors with kinase activity.
`In the structure of the receptor tyrosine kinases, an extracellular ligand-binding domain
`occurs which is connected to an intracellular catalytic kinase domain byasingle pass
`transmembrane hydrophobic helix [27]. RTKs are not phosphorylated and monomeric in
`an inactive state [29]. Activation by ligand bindingto their extracellular domain results in
`receptors’ oligomerization and autophosphorylation of a tyrosine residue within the kinase
`domain. NRTKsare cytoplasmic proteins that have a kinase domain andvarious additional
`signaling or protein-protein interacting domains[27]. They are activated by intracellular
`signals throughthe dissociation of inhibitors, by recruitment to transmembranereceptors,
`and throughtrans-phosphorylation by other kinases [29]. A large number of RTKs and
`NRIKsare associated with cancers; thus, a significant numberof tyrosine kinase inhibitors
`(TKIs) are currently in clinical development. In the last 10 years, the FDA has approved
`four new drugsfor the treatment of hematological malignancies, which are tyrosine kinase
`inhibitors (Table 1). Among them,there are the agents that target non-receptor Bruton’s
`tyrosine kinase (BTK) or non-receptor Sarcoma(Src) and Abelson (Abl) kinases.
`Ibrutinib, acalabrutinib, and zanubrutinib were originally developed as second-line
`therapy for the treatment of mantle cell lymphoma (MCL), a rare and aggressive type of
`blood cancer. To date, ibrutinib has received 11 FDA approvalssinceit wasfirst regis-
`tered in 2013, amongothers, as a breakthrough therapy for patients with Waldenstrém’s
`macroglobulinemia (WM)and chronic lymphocytic leukemia (CLL), who carry a deletion
`in chromosome17 (17p deletion). In 2019, the FDA approved ibrutinib in combination
`with obinutuzumab, an anti-CD20 monoclonal antibody, as the first non-chemotherapy
`regimen for patients with previously untreated CLL [30]. In the same year, acalabruti-
`nib received approval as the second BTK inhibitor to treat patients with CLL or small
`lymphocytic lymphoma (SLL). This drug can be used as monotherapy or in combina-
`tion with obinutuzumab [31]. The mechanism ofaction of ibrutinib, acalabrutinib, and
`zanubrutinibis the irreversible inhibition of BTK activity by forming a covalent bond with
`a cysteine residue in the BTK active site. This results in blocking B cell antigen receptor
`signaling(i.e., nuclear factor of activated T-cells (NFAT) pathway, nuclear factor kappa-
`light-chain-enhancerof activated B cells (NF-KB) pathway, and mitogen-activated protein
`kinase (ERK) pathway), thus inhibiting the malignantB cells’ proliferation and survival
`(Figure 1) [32-34].
`Bosutinib is a dual inhibitor of Src and Abl kinases that is used as a treatment for
`patients with Philadelphia chromosomepositive (Ph+) chronic myeloid leukemia (CML),
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`whoshowresistance or intolerance to previous therapy, including imatinib. The indication
`was extendedin 2017 to include patients with newly diagnosed chronic phase Ph+ CML [35].
`The drug showsactivity against most imatinib-resistant mutants of BCR-ABL, whichis
`a hybrid of a breakpoint cluster region protein (BCR) and Abelson tyrosine kinase (Abl),
`except the mutations T315] and V299. Bosutinib does not inhibit either the receptor tyrosine
`kinase c-Kit (known as mast/stem cell growth factor receptor or CD117) orplatelet-derived
`growth factor receptor (PDGFR) [36]. The drug acts by bindingto the active conformation
`of the kinase domain andinhibiting its autophosphorylation, resulting in a blockade of
`cancercell growth (Figure 1) [37].
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`Figure 1. Modeofaction of tyrosine kinase (TK) inhibitors such as non-receptor BTK and Src/AbIin-
`hibitors. BCR: B-cell receptor. RTK:tyrosine kinase receptor. RAF: proto-oncogeneserine /threonine-
`protein kinase. MEK: mitogen-activated protein kinase kinase. ERK: mitogen-activated protein
`kinase. Sre: non-receptor Sarcoma kinase. Abl: Abelson kinase. Rac: Ras-related C3 botulinum
`toxin substrate. JNK: c-Jun N-terminal kinase. SYK: spleen tyrosine kinase. BCAP: B cell adapter
`for PI3K. DAG:diacylglycerol. PKC: protein kinase C. IKK: IkB kinase. NF-«B: nuclear factor
`kappa-light-chain-enhancerof activated B cells. Lyn: tyrosine-protein kinase Lyn. BTK: Bruton’s
`tyrosine kinase. PLC: phospholipase C. IP3: inositol trisphosphate. NFAT: nuclear factor of activated
`T-cells. Created with BioRender.com based on informationin [37,38].
`
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`6 of 64
`Cancers 2022, 14, 87
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`
`2.1.2. Multi Kinase Inhibitors
`
`Multi kinase inhibitors are a group of ATP-competitive drugs that target a set of
`structurally related kinases. A single multi-inhibitor is preferred to two single inhibitors
`since drug-drug interactions might occur, changing the metabolism andactivities against
`particular kinases. Multi kinase drugs becomethe second choice when their pharmacoki-
`netic properties are worse. Besides, multi kinase inhibitors are less specific and might
`consequently lead to more side effects. A frequently observed disadvantage duringtreat-
`ment with multi kinase inhibitors is acquired resistance [48]. However, the inhibition
`of several kinases by one drugis useful in anticancer therapy, because oncogenesis and
`cancer growthhaveto be considered as multistep processes that are dependenton various
`signaling pathways(Figure 2) [49]. An overview of FDA-approved multi kinase inhibitors
`is presented in Table 2.
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`Figure 2. Schematic representation of the signaling pathwaysthat can potentially be inhibited by
`multi kinase inhibitors. BCR: B-cell receptor. PDGFR:platelet-derived growth factor receptor. FLT3:
`FMS-like tyrosine kinase-3. AXL: AXL receptor tyrosine kinase. ALK: anaplastic lymphoma ki-
`nase. VEGFR:vascular endothelial growth factor receptor. FGFR:fibroblast growth factor receptor.
`RET:receptor tyrosine kinase rearranged during transfection. c-Kit: mast/stem cell growth fac-
`tor receptor. TIE2: tunica interna endothelial cell kinase 2. PI3K: phosphatidylinositol 3-kinase.
`PIP2: phosphatidylinositol 4,5-bisphosphate. PIP3: phosphatidylinositol-3,4,5-trisphosphate. PTEN:
`phosphatase and tensin homolog deleted on chromosome ten. PDK: 3-phosphoinositide-dependent
`protein kinase. AKT: protein kinase B. mTORC1: mammalian target of rapamycin complex 1. 4E-
`BP1: 4E-binding protein 1. eIF4E: eukaryotic translation initiation factor 4E. S6K: p70S6 kinase.
`S6: S6 protein. RAF: proto-oncogeneserine/threonine-protein kinase. MEK: mitogen-activated
`protein kinase kinase. ERK: mitogen-activated protein kinase. Sre: non-receptor Sarcoma kinase.
`Abl: Abelson kinase. Rac: Ras-related C3 botulinum toxin substrate. JNK: c-Jun N-terminal kinase.
`CDK:cyclin-dependent kinase. SYK: spleen tyrosine kinase. BCAP:Bcell adapter for PI3K. DAG:
`diacylglycerol. PKC: protein kinase C. IKK: IkB kinase. NF-«B: nuclear factor kappa-light-chain-
`enhancerof activated B cells. Lyn: tyrosine-protein kinase Lyn. BTK:Bruton’s tyrosine kinase. PLC:
`phospholipase C. IP3: inositol trisphosphate. NFAT:nuclear factorof activated T-cells. Created with
`BioRender.com based on information in [37,38,50,51].
`
`

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`The kinase domain mutationsare the reason for developing drugresistance during the
`treatmentof various types of leukemia. One of the most commongenetic alterations is the
`gatekeeper T315] substitution observed in chronic myeloid leukemia (CML) or Philadelphia
`chromosomepositive (Ph+) acute lymphoblastic leukemia (ALL) and FMS-like tyrosine
`kinase-3 (FLT3)-activating mutations in acute myeloid leukemia (AML). Resistance to tyro-
`sine kinase inhibitors has necessitated the designing of new mutation-resistant inhibitors,
`such as ponatinib, midostaurin, and gilteritinib. Ponatinib is a multitarget inhibitor char-
`acterized by high-affinity and optimized bindingto the active site of the BCR-ABL kinase
`domain, in which the T315 can occur. This mutation is the major reason for inhibition
`access of the drug to the enzyme’s ATP-bindingsite, leading to resistance to first- and
`second-generation tyrosine kinase inhibitors [52]. Ponatinib is effective in the inhibition
`of native and mutant BCR-ABL,receptor tyrosine kinase rearranged during transfection
`(RET), FLT3, tunica interna endothelial cell kinase 2 (TIE2), mast/stem cell growth factor
`receptor (c-Kit), vascular endothelial growth factor receptors (VEGFRs), fibroblast growth
`factor receptors (FGFRs), and platelet-derived growth factor receptors (PDGFRs). Treat-
`ment with ponatinib showssubstantial and durable clinical activity in patients with Ph+
`leukemia with resistance or intoleranceto all other approvedtyrosine kinaseinhibitors [53].
`Adverse events of this therapy are defined as follows: nonhematologic toxic effects such
`as skin disorders(e.g., rash, acneiform dermatitis, and dry skin), constitutional symptoms
`(e.g., arthralgia, fatigue, and nausea), or hematologic—suchas vascular occlusive—events,
`venous thromboembolic events, thrombocytopenia, and neutropenia [52]. The occurrence
`of vascular events during therapy was dependenton the dose of ponatinib, wherein lower
`doses have affected the improvementof the vascular safety profile [54]. Midostaurin
`and gilteritinib are approved drugs for patients with newly diagnosed FLT3-mutated
`AML.Theclinical activity of midostaurin in combination with cytarabine and daunoru-
`bicin-based chemotherapy waspositive for FLT3-activating mutations, such as, primarily,
`in-frame internal tandem duplications (ITD) and missense point mutations in the tyro-
`sine kinase domain (TKD). Moreover, midostaurin inhibits c-Kit (wild type and D816V
`mutant) found in advanced systemic mastocytosis (SM), which includes aggressive sys-
`temic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm
`(SM-AHN), and mastcell leukemia [55]. It was found to also be an inhibitor of protein
`kinase C (PKC), platelet-derived growth factor receptors (PDGFRs) alpha andbeta, cyclin-
`dependentkinase 1 (CDK1), spleen tyrosine kinase (SYK), and vascular endothelial growth
`factor receptor-2 (VEGFR-2) [56]. Although midostaurin showsa broad spectrum of an-
`tikinase activity, it is characterized by lacked potency. Gilteritinib, on the other hand,is
`a selective, potent inhibitor of all FLT3-activating mutation types(e.g., ITC, TKD, D835Y,
`double ITD-D835Y) [57]. Furthermore, gilteritinib showsactivity against c-Kit and the
`AXLreceptor tyrosine kinase (AXL, also known as UFO), whichis implicated in FLT3
`inhibitor resistance [58]. The mechanism ofaction of gilteritinib involves bindingto the
`active conformation of FLT3 at the ATP-bindingsite, resulting in reduced proliferation of
`cancercells that overexpress the mutation [59].
`The mutations that confer activation of the intracellular Janus kinase (JAK) signal
`transducer andactivator of transcription (STAT) pathways(e.g., JAK2, V617F, and JAK2
`exon 12) were identified as the most commonin patients with myelofibrosis (MF). Only two
`drugs, namely ruxolitinib and fedratinib, are approved as JAKinhibitors for the treatment
`of MF [60]. Ruxolitinib is a JAK1/2 inhibitor that potently inhibits the proliferation of
`JAK2 V617F-driven Ba/F3cells, resulting in decreased levels of phosphorylated JAK2 and
`signal transducer and activator of transcription 5 (STAT5) [61]. Ruxolitinib provides a
`rapid reduction in splenomegaly, ameliorating debilitating myelofibrosis-related symptoms
`and improving quality of life in patients with MF. The adverse events of ruxolitinib, like
`anemia and thrombocytopenia, were manageable andled to the discontinuation of therapy
`at a low rate [62]. Ruxolitinib is also an effective drug for patients with polycythemia
`vera, which allows for hematocrit control, reducing spleen size, and improving symptoms
`of disease [63]. However, some patients lose response to ruxolitinib and discontinue
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`treatment over time because developing resistance or intolerance is associated with a
`substantially reduced life expectancy. Fedratinib, an alternative approved JAK inhibitor,
`is potent and selective for JAK2 regardless of its mutational status [64]. Compared with
`ruxolitinib, fedratinib causes a more effective reduction in spleen volume anddisease-
`related symptoms[65].
`
`

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`

`11 of 64
`Cancers 2022, 14, 87
`
`2.2. Phosphatidylinositol 3-Kinase (PI3K) Inhibitors as Anticancer Agents
`Phosphatidylinositol 3-kinases (PI3Ks) are a family oflipid kinases that phosphorylate
`phosphoinositides at the 3-hydroxyl group ofthe inositol ring that can be used to generate
`phosphatidylinositol 3,4,5-trisphosphate. Amongthese, several classes have been identified
`and characterized by different primary structures and substrate specificities. Class I PI3Ks
`are heterodimers and divide into two groups, IA andIB. Class IA PI3Ksare activated by
`a wide rangeof receptor tyrosine kinases (RTKs) and are frequently implicated in cancer,
`while class IB PI3Ks are activated by G-protein-coupled receptors [77]. Structurally, class
`IA PI3Ksexists in three isoforms («, 8, and 5) and class IB PI3Ksin one isoform (vy). Class
`II PI3Ks are monomeric proteins that consist of three isoforms («, 8B, and 5), whereas
`class III PI3Ks are only one heterodimer composedof a catalytic (Vps34) and regulatory
`subunit [78]. PI3K-related kinases, which can be includedasclass IV of PI3K, are a group of
`protein kinases with structural similarity to PI3K, but withoutthelipid kinase activity. This
`group includes a mammalian target of rapamycin (mTOR), DNA-dependentprotein kinase
`(DNA-PK), ataxia telangiectasia mutated gene product (ATM), and ataxia telangiectasia
`and Rad3-related gene product[79]. The dysregulation of the phosphatidylinositol-3 kinase
`pathway, especially abnormal activation, is one of the most frequently observed in blood
`cancers and an importanttarget of selective anticancer therapies. The three inhibitors of
`PI3K havereceived market approval since 2011 (Table 3). Idelalisib, a first-in-class inhibitor
`of PI3K-5, and the following inhibitors, i.e., copanlisib and duvelisib, directly reduce the
`proliferation and survival of malignant B-cell leukemia and lymphomacells (Figure 3).
`Hence, they were approved by the FDA for the treatment of different types of leukemia
`and lymphoma[80-82]. Duvelisib is a first-in-class dual inhibitor of PI3Ks dueto the fact
`that it also inhibits PI3K-y activity, which leadsto a reductionin the differentiation and
`migration of various components of the cancer microenvironment, such as T helpercells
`and M2 tumor-associated macrophages[82]. It is worth noting that the route of copanlisib
`administration as intermittent intravenousinfusions lead to weaker gastrointestinal toxicity
`compared with the oral treatmentof idelalisib [83].
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`Figure 3. Mechanism of action of PI3K inhibitors. RTK: receptor tyrosine kinase. PI3K: phos-
`phatidylinositol 3-kinase. PIP2: phosphatidylinositol 4,5-bisphosphate. PIP3: phosphatidylinositol-
`3,4,5-trisphosphate. PTEN: phosphatase and tensin homolog deleted on chromosometen. PDK:
`3-phosphoinositide-dependentprotein kinase. AKT: protein kinase B. mTORC1: mammaliantarget
`of rapamycin complex 1. 4E-BP1: 4E-binding protein 1. eIF4E: eukaryotic translation initiation factor
`4E. S6K: p70S6 kinase. S6: S6 protein. Created with BioRender.com based on information in [51,79].
`
`

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`13 of 64
`Cancers 2022, 14, 87
`
`2.3. Various Enzymes Inhibitors as Anticancer Agents
`Enzymesare organic high-molecular-weight molecules that catalyze the synthesis or
`degradation reaction of a specific enzyme’s substrate. Enzymeinhibitors bind to the
`enzyme, resulting in disruption of the normal format