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Protein Kinase Inhibitors As Therapeutic Drugs in AML: Advances and Challenges No

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Protein Kinase Inhibitors As Therapeutic Drugs in AML: Advances and Challenges No Send Orders for Reprints to [email protected] 4303 Current Pharmaceutical Design, 2017, 23, 4303-4310 REVIEW ARTICLE ISSN: 1381-6128 eISSN: 1873-4286 Protein Kinase Inhibitors as Therapeutic Drugs in AML: Advances and Challenges no. Impact Factor: 2.611 BENTHAM SCIENCE Yuan Linga,b, Zikang Zhanga,b, Hua Zhanga,b,* and Zunnan Huanga,b,* aGuangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, P.R. China; bChina-America Cancer Research Institute, Dongguan Key Laboratory of Epigenetics, Institute of Clinical Laboratory Medicine, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan 523808, P.R. China Abstract: Acute myeloid leukemia (AML) is a malignant blood disorder and the cure rate has been remarkably improved over the past decade. However, recurrent or refractory leukemia remains the major problem of the A R T I C L E H I S T O R Y AML and no clearly effective therapy has been established so far. Traditional treatments such as chemotherapy and hematopoietic stem cell transplantation are both far dissatisfying the patients partly for their individual vari- ety. Besides, conventional treatments usually have many side effects to result in poor prognosis. Therefore, an Received: April 24, 2017 Accepted: May 18, 2017 urgent need is necessary to update therapies of AML. To date, protein kinase inhibitors as new drugs offer hope for AML treatment and many of them are on clinical trials. Here, this review will provide a brief summary of protein kinase inhibitors investigated in AML thus far, mainly including tyrosine protein kinase inhibitors and DOI: serine/threonine kinase inhibitors. We also presented the sketch of signal pathways involving protein kinase in- 10.2174/1381612823666170703164114 hibitors, as well as discussed the clinical applications and the challenges of inhibitors in AML treatment. Keywords: Acute myeloid leukemia, protein kinase, inhibitor, therapy, drug, FLT3, mTOR. 1. INTRODUCTION resistant of the first generation of inhibitors, emerging effective Acute myeloid leukemia (AML) is a kind of clonal disorders of therapies with recently designed compounds appear promising. In malignant hematopoietic stem cells, remarkably characterized by this review, we will provide a comprehensive overview of AML, the accumulation of primitive or immature leukemia cells in bone kinase and kinase inhibitors, especially summarize the protein marrow and peripheral blood, resulting in inducing the disease and kinase inhibitors currently studied and developed in AML including hampering the clinical treatment [1, 2]. When AML happened, the tyrosine protein kinase inhibitors and serine/threonine kinase inhibi- red blood cells, platelets and normal white blood cells became less, tors. while the immature cells multiply accumulated, which further inter- 2. THE DEVELOPMENT AND THERAPY OF AML fered with the normal bone marrow hematopoietic function. Based on clinical observation and related trials [3], it is commonly ac- In 1900, leukemia has been divided into myeloid or lympho- cepted that AML is a kind of refractory type of bone marrow cancer cytic leukemia according to the origin of the diseased red cells and with poor prognosis and more commonly affects the elderly patients non-lymphoid white blood cells (called the myeloid pathway) or a over 60 [4]. precursor of T and B cells (called the lymphoid pathway) [14]. Seventy-six years later, the French-American-British (FAB) classi- Although the recent advancement in understanding the treat- fication system classified AML into eight subtypes, M0 to M7 [15]. ment of AML has remarkably improved the cure rate over the past The World Health Organization (WHO) classification of tumors of decade [5]; however, the 5-year survival rates of patients are only hematopoietic and lymphoid tissues, determining the types of AML about 40% for young/middle-aged patients and less than 10% for based on the morphology and prognosis, was updated in 2008 and elderly patients [6, 7]. The big difference between them might be put up with the relative targeted therapy [16]. Clinically, doctors caused by the inherently poor physical condition and more resistant often adopt applicable treatment on the basis of the classification leukemia cells for elderly patients, which lead to worse prognosis and patient’s own physical condition. According to the National [2, 4, 8, 9]. In recent years, due to an aging population, the inci- Comprehensive Cancer Network (NCCN) Guidelines Version dence of AML appears to be rising [4]. Encouragingly, the devel- 1.2016 (Table 1) [17], the mutation of Fms-like tyrosine kinase3- opment of genomics and sequencing technology makes us have a intenal tandem duplication (FLT3-ITD), tumor protein 53 (TP53), better understanding of molecular genetic mutation and the patho- c-KIT, NPM1 and CCAAT/enhancer-binding protein alpha genesis of AML [10]. Furthermore, the targeted therapy has been (CEBPA) are all likely to add risk to AML, which may contribute becoming the most promising therapeutic approache [11, 12]. Espe- to AML recurrence. cially, the key protein kinases as drug screening targets have shown effectives and become a focus [13]. Among the current clinical The conventional method in the treatment of AML aims to take application of pharmacological targets in AML, kinase inhibitors advantage of the toxic compounds, namely chemotherapy drugs, to account for the most, particularly tyrosine kinase inhibitors. kill leukemia cells. However, the chemotherapy drugs surely ulti- mately attack the human’s normal immune cells, thus, it is hard to Developing new targeted drugs with high efficiency, low toxic- achieve the aim of complete remission (CR), which means no sign ity, strong specificity has become an attractive area of antitumor of poor symptom in patients and their returning to good health. research. In spite of the mutation of the protein kinase and the drug During the formal therapy, it is expected to reduce more leukemia cells to an undetectable level to achieve a complete remission and *Address correspondence to these authors at the Guangdong Provincial Key the goal of consolidation therapy is to eliminate any residual unde- Laboratory of Medical Molecular Diagnostics, Guangdong Medical Univer- tectable disease and achieve a cure [18]. Young patients often can sity, Dongguan, P.R. China; E-mails: [email protected] (Hua tolerate this kind of chemotherapy, but the tolerance to intensive Zhang); [email protected] (Zunnan Huang) chemotherapy will decrease with age. Adverse reaction to treat- Current Pharmaceutical Design 1873-4286/17 $58.00+.00 © 2017 Bentham Science Publishers G 4304 Current Pharmaceutical Design, 2017, Vol. 23, No. 29 Ling et al. Table 1. Risk status based on validated cytogenetics and molecular abnormalities. Risk status Cytogenetics Molecular Abnormalities Core binding factor: inv(16) or t(16; 16) or t(8; 21) or t(15; Normal cytogenetics: Favorable-risk 17) NPM1 mutation in the absence of FLT3-ITD or isolated biallelic double CEBPA mutation Intermediate-risk Normal cytogenetics Core binding factor with KIT mutation +8 alone t(9; 11) Other non-defined Complex (≥3 clonal chromosomal abnormalities) Monosomal karyotype Normal cytogenetics: -5, 5q-, -7, 7q- with FLT3-ITD mutation 11q23 - non t(9; 11) TP53 mutation Poor-risk inv(3), t(3; 3) t(6; 9) t(9; 22) (NCCN - Evidence-Based Cancer Guidelines, Oncology Drug Compendium, Oncology Continuing Medical Education https: //www.nccn.org//) ment, low induced relieving rate, high recurrence rate, and short due to the emergence of many new mutation sites of new targets survival period are tough problems that need to be solved in the (Fig. 2). Besides the efforts to screen more related key enzyme treatment of AML. targets, developing more stable and specific inhibitors is also ur- Although chemotherapy will help to reduce tumor size, pro- gently needed. longing the use of chemotherapy would not result in more cancer 3. PROTEIN KINASE INHIBITORS destruction. In addition, it is hard to identify the diagnosis, stage and evaluate the treatment effect in AML. Thus, unnecessary che- Protein kinase is a kind of protein phosphotransferase bringing motherapy, usually with high costs as well as side effects, makes it the phosphate of ATP to the specific amino acid residue. It may fail to cure AML. Moreover, the cancer cells may eventually de- conventionally be divided into five classes: tyrosine protein kinase, velop resistance to multiple chemotherapeutics. For patients who serine/threonine protein kinase, histidine protein kinase, tryptophan are intolerant to standard chemotherapy, reducing the dose of in- protein kinase and aspartyl/glutamoyl protein kinase. Protein duction chemotherapy regimens would greatly decrease the com- kinases are associated with constitutive activation of many down- plete remission rate, specially for the recurrent AML. Despite a stream pathways, such as phosphatidyl-inositol 3-kinase/v-akt mur- variety of clinical trials of new drugs, there is no breakthrough in ine thymoma viral oncogene homolog 1 (PIK3/AKT), mitogen- classic “3 + 7” scheme of anthracycline-based drugs combined with activated protein kinase/extracellular signal regulated kinase cytarabine. Hematopoietic stem cell transplantation (HSCT) is usu- (MAPK/ERK) and signal transducer and activator of transcription 5 ally considered if induction chemotherapy fails or AML relapses, (STAT5) [23-25]. Protein kinases can regulate many kinds of signal however, the seriously
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