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Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action

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Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action International Journal of Molecular Sciences Review Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action Paweł Łukasik 1, Irena Baranowska-Bosiacka 2, Katarzyna Kulczycka 3 and Izabela Gutowska 1,* 1 Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powstancow Wlkp. 72 Av., 70-111 Szczecin, Poland; [email protected] 2 Department of Biochemistry, Pomeranian Medical University in Szczecin, Powstancow Wlkp. 72 Av., 70-111 Szczecin, Poland; [email protected] 3 Department of Pharmaceutical Chemistry, Pomeranian Medical University in Szczecin, Powstancow Wlkp. 72 Av., 70-111 Szczecin, Poland; [email protected] * Correspondence: [email protected] Abstract: Recent studies on cyclin-dependent kinase (CDK) inhibitors have revealed that small molecule drugs have become very attractive for the treatment of cancer and neurodegenerative disorders. Most CDK inhibitors have been developed to target the ATP binding pocket. However, CDK kinases possess a very similar catalytic domain and three-dimensional structure. These features make it difficult to achieve required selectivity. Therefore, inhibitors which bind outside the ATP binding site present a great interest in the biomedical field, both from the fundamental point of view and for the wide range of their potential applications. This review tries to explain whether the ATP competitive inhibitors are still an option for future research, and highlights alternative approaches to discover more selective and potent small molecule inhibitors. Keywords: cyclin-dependent kinase inhibitors; cancer; cell cycle; CDKs; CDK inhibitors Citation: Łukasik, P.; Baranowska-Bosiacka, I.; Kulczycka, K.; Gutowska, I. Inhibitors of Cyclin-Dependent Kinases: Types 1. Cyclin-Dependent Kinases (CDKs) and Their Mechanism of Action. Int. J. Mol. Sci. 2021, 22, 2806. https:// Protein phosphorylation is a necessary mechanism to drive numerous cellular pro- doi.org/10.3390/ijms22062806 cesses such as cell division, migration, differentiation and programmed cell death. This process is regulated by many enzymes, including cyclin-dependent kinases (CDKs) which Academic Editor: Antonio Giordano phosphorylate proteins on their serine and threonine amino acid residues. The 20 members of CDK family known to this day regulate the cell cycle, transcription and splicing [1]. A Received: 12 February 2021 number of kinase inhibitors are emerging every day as potential small molecule drugs, Accepted: 5 March 2021 with some of them already being approved by the United States Food and Drug Admin- Published: 10 March 2021 istration (FDA). Moreover, these already approved kinase targeting drugs now account for more than a quarter of all available drugs [2]. In relation to CDK inhibitors, drugs Publisher’s Note: MDPI stays neutral such as Palbociclib 1, Ribociclib 2 and Abemaciclib 3, have been approved for ER+/HER2- with regard to jurisdictional claims in advanced breast cancer treatment [3]. Until recently, the focus of the research was aimed published maps and institutional affil- at the highly conserved ATP binding sites of each CDK kinase. Hence, the development iations. of CDK inhibitors has been extremely challenging due to the difficulty of obtaining suffi- cient selectivity with typical ATP-mimetic compounds. The greatest number of reported compounds has been identified to target the ATP binding pocket. Most recent studies suggest that inhibitors targeting hydrophobic pockets outside the ATP binding site may Copyright: © 2021 by the authors. provide an opportunity for rational target selectivity [4]. Figure1 illustrates the typical Licensee MDPI, Basel, Switzerland. protein structure of the CDK enzyme. The diagram depicts the structural features of a This article is an open access article typical kinase domain. Specifically highlighted are the binding pockets of different types distributed under the terms and of inhibitors, as well as the activation loop. conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 2806. https://doi.org/10.3390/ijms22062806 https://www.mdpi.com/journal/ijms Int.Int. J. J. Mol. Mol. Sci. Sci. 20212021,, 2222,, x 2806 FOR PEER REVIEW 22 of of 23 24 FigureFigure 1. 1. SSchematicchematic representation representation of different typestypes ofof bindingbinding pockets. pockets. The The protein protein kinase kinase is is shown shownin blue, in with blue, the with Asp-Phe-Gly the Asp-Phe (DFG)-Gly (DFG) motif motif in green. in green. Red colorRed color denotes denotes the aspartatethe aspartate amino amino acid acidresidue residue of the of DFG the DFG motif. motif. The particular The particular regions regions where where different different types oftypes inhibitors of inhibitors bind are bind described are described below, the allosteric pocket is only a visualization and its place can be anywhere outside below, the allosteric pocket is only a visualization and its place can be anywhere outside the ATP the ATP binding site. binding site. 2.2. Cyclin Cyclin-Dependent-Dependent Kinase Kinase (CDK) (CDK) Inhibitors Inhibitors in in Drug Drug Development Development CDKCDK family family is isknown known to toregulating regulating the thecell cellcycle, cycle, transcription transcription and splicing. and splicing. Deregulation Dereg- ofulation any of ofthe any stages of theof the stages cell cycle of the or cell transcription cycle or transcription leads to apoptosis leads but, to apoptosisif uncorrected, but, it if canuncorrected, result in a series it can of result diseases in asuch series as cancer of diseases or neurodegenerative such as cancer diseases or neurodegenerative [1,5–7]. diseasesWithin [1,5 the–7]. last 20 years important advances have been achieved in the development of effectiveWithin strategies the last 20 to years inhibit important CDK kinases. advances Access have of been the substrate achieved into the developmentactive site of CDKof effective kinase is strategies regulated to by inhibit the activation CDK kinases. loop (A Access-loop) which of the is substrate very flexible. to the The active A-loop site containsof CDK be kinasetween is 20 regulated–30 amino by acids the activationmarked by loopthe conserved (A-loop) whichAsp-Phe is- veryGly (DFG) flexible. tripep- The tideA-loop motif contains at the proximal between 20–30end. Phosphorylation amino acids marked of the by activation the conserved loop activates Asp-Phe-Gly the kinase. (DFG) Intripeptide this state motif, the DFG at the sequence proximal fits end. snugly Phosphorylation into a hydrophobic of the activation back pocket loop adjacent activates to the the ATPkinase. binding In this site. state, Conversely, the DFG sequence in the inactive fits snugly state into the a hydrophobicDFG motif swings back pocket outwards adjacent by partiallyto the ATP blocking binding both site. the Conversely, ATP and substrate in the inactive binding state pockets the DFG [8]. motif swings outwards by partiallyTo date, blocking six types both of small the ATPmolecule and substrate kinase inhibitors binding pocketshave been [8]. defined by the phar- maceuticalTo date, industry six types based of small on their molecule biochemical kinase inhibitorsmechanisms have of beenaction defined (Figure by 2) the. Type phar- I inhibitorsmaceutical interact industry directly based with ontheir the ATP biochemical binding site mechanisms and react ofwith action the active (Figure form2). Type of the I kinaseinhibitors which interact is in the directly DFG- within state the and ATP with binding a phosphorylated site and react withactivation the active loop form(activation of the segmekinasent). which These is ininhibitors the DFG-in mimic state the and hydrogen with a phosphorylated bonds created activationbetween the loop adenine (activation ring ofsegment). the ATP Theseand the inhibitors hinge region mimic of the the hydrogen enzyme. Type bonds II created inhibitors between interact the with adenine a DFG ring-out of catalyticallythe ATP and inactive the hinge conformation region of the of enzyme.the enzyme Type and, II inhibitors like type interactI inhibitors, with explore a DFG-out the hingecatalytically region and inactive the adenine conformation binding of pocket. the enzyme Type III and, inhibitors like type are I inhibitors,non-competitive explore with the ATPhinge as region they bind and theto the adenine hydrophobic binding pocket pocket. next Type to III the inhibitors ATP-binding are non-competitive site, while type with IV inhibitorsATP as they bind bind away to the from hydrophobic the ATP binding pocket pocket. next to theBoth, ATP-binding type III and site, IV in whilehibitors type are IV allostericinhibitors in bind nature away [8]. fromType theV inhibitors ATP binding interact pocket. with Both,two separate type III regions and IV of inhibitors the protein are kinaseallosteric domain. in nature This [8 ].group Type Vof inhibitorsinhibitors interact has been with classified two separate as bi regions-substrate of theinhibitors. protein Thesekinase five domain. classes This of inhibitors group of inhibitors interact reversibly, has been classified while type as VI bi-substrate inhibitors inhibitors. form a covalent These bondfive classes with their of inhibitors target kinase interact (Figure reversibly, 2) [9]. while type VI inhibitors form a covalent bond with their target kinase (Figure2)[9]. Int.Int. J. Mol. J. Mol. Sci. Sci. 20212021, 22,22 x FOR PEER REVIEW 3 of 23 , , 2806 3
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