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The Protein Kinase Inhibitor Balanol: Structure–Activity Relationships and Structure-Based Computational Studies

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The Protein Kinase Inhibitor Balanol: Structure–Activity Relationships and Structure-Based Computational Studies 638 Anti-Cancer Agents in Medicinal Chemistry, 2008, 8, 638-645 The Protein Kinase Inhibitor Balanol: Structure–Activity Relationships and Structure-Based Computational Studies Vineet Pande1,§, Maria J. Ramos1 and Federico Gago2,#,* 1REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto, 4169-007, Porto, Portu- gal; 2Departamento de Farmacología, Universidad de Alcalá, Alcalá de Henares, 28871, Madrid, Spain and §Present Address: Computational Lead Discovery, AstraZeneca R&D Mölndal, Sweden SE-431 83 Abstract: Balanol, a fungal metabolite, is a potent ATP-competitive inhibitor of Protein Kinase C (PKC) and Pro- tein Kinase A (PKA), important targets in oncology. Since its discovery in 1993, a number of studies have been per- formed in order to design selective and bioavailable balanol analogs. Several crystal structures of PKA in complex with balanol and a few analogs bound within the catalytic site have also been solved providing insight about the key interactions for binding. The PKA-balanol complex has also served as an interesting model system for structure- based ligand design and validation of a number of computational methodologies aimed at both understanding the physical basis for molecular recognition and addressing the important issue of protein flexibility in ligand binding. We provide an overview of the structure-activity relationships of balanol analogs and summarize the progress made in structural and computational studies involving balanol. Key Words: Balanol, structure activity relationships, kinases, computational chemistry, x-ray crystal structure, protein flexibility, adenosine triphosphate. #Author Profile: Federico Gago studied Pharmacy at Complutense University in Madrid, completed his Ph. D. in Alcalá University, and pursued postdoctoral studies in Oxford University, UK. He is currently Associate Professor of Pharmacology, with research interests in the areas of molecular modelling, drug de- sign, structure-activity relationships, and computer simulations of ligand-receptor complexes. 1. INTRODUCTION isoforms, which vary in both tissue expression and cellular com- Protein kinases belong to a diverse family of enzymes that have partmentalization [9]. PKC is a major receptor for tumor-promoting various regulatory roles, yet function similarly by catalyzing the phorbol esters, which activate PKC in a way similar to DAG, and phosphoryl transfer of the -phosphate of adenosine triphosphate unregulated PKC activity has been related to a number of disease (ATP) to an enzyme-specific protein substrate. Since many diseases states including cancer, central nervous system disturbances, car- including cancer, autoimmune disorders, cardiac disease and diabe- diovascular disorders, asthma, diabetes and HIV infections [10]. tes are associated with defects in protein phosphorylation and there Apart from inhibiting PKC, balanol is a potent inhibitor of cyclic are over 500 protein kinases in the human genome, this family (the AMP-dependent protein kinase (PKA), another similar serine/ “kinome”) has emerged as a major target in the design and devel- threonine kinase important in physiology [11]. Balanol does not, opment of small molecule inhibitors [1-3]. One such inhibitor is the however, inhibit the Src or epidermal growth factor receptor protein natural product balanol (1), which has been consistently employed tyrosine kinases [11, 12]. for the last 14 years, not only as a lead molecule, but also as a Mechanistically, balanol inhibits PKC and PKA because it model compound by experimentalists as well as computational binds in the ATP binding pocket of these kinases with an affinity chemists. The purpose of this report is to present a comprehensive that is 3000 times greater than that of ATP (Ki value of balanol for account of the structure-activity relationships (SARs) of balanol both PKA and PKC is around 4 nM) [12]. We will discuss in detail analogues and an overview of how X-ray crystallography and com- this competitive inhibition with ATP in a later section on structural putational chemistry have contributed to our understanding of the studies on PKA/PKC-balanol complexes. Fig. (2) shows the three- issues of selectivity and protein flexibility in kinase inhibition using dimensional structures of balanol and ATP. Stereoelectronically, balanol as a model compound. balanol is similar to ATP and also binds to an equivalent cleft in the Balanol (Fig. 1), a fungal metabolite originally isolated and kinase active site: the p-hydroxybenzamide group of balanol re- identified in 1993 from Verticillium balanoides, is regarded as one sembles the adenine base, the perhydroazepine ring resembles the of the most potent naturally occurring inhibitors of Protein Kinase ribose moiety, and the benzophenone resembles the triphosphate C (PKC) [4]. PKC encompasses a family of structurally related group. Balanol extracted from fungus is obtained in very low yield serine/threonine specific kinases widely distributed in tissues and and, as early as 1994, two groups reported its total synthesis [13, cells [5]. PKC is activated by diacylglycerol (DAG) originating 14]. Since then a number of studies have been devoted entirely to from receptor-mediated hydrolysis of membrane inositol phosphol- developing a more efficient synthesis of balanol and its enantiomers ipids, a process that is responsible for initiating a cascade of cellular and analogues [15-38]. To review the synthetic chemistry of these responses to extracellular stimuli such as hormones, neurotransmit- molecules falls beyond the scope of this article, but we emphasize ters, and growth factors [6, 7]. Activated PKC catalyzes the transfer that balanol has been seen by organic chemists in the last decade as of the -phosphate of ATP to substrate proteins and, by doing so, a challenging heterocyclic scaffold for synthetic purposes and also relays transmembrane signals to biological systems involved in a for structural modification. This endeavor, on the whole, has proved number of cellular processes including gene expression, cell prolif- to be both successful and rewarding [39, 40]. eration and differentiation [8]. Further, PKC has at least 10 different 2. STRUCTURE ACTIVITY RELATIONSHIPS Balanol has been extensively modified, mainly in order to de- *Address correspondence to this author at the Departamento de Farmacolo- sign not only PKC or PKA selective analogs (or even analogues gía, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain; selective for some PKC isoforms) but also inhibitors with improved E-mail: [email protected] 1871-5206/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. The Protein Kinase Inhibitor Balanol Anti-Cancer Agents in Medicinal Chemistry, 2008, Vol. 8, No. 6 639 OH OH O O O COOH HN S CF3 O O O O OH HO O OH HO HO H N HO H N O N 1 2 H O N NCH3 N NH OH N OH O N O N N O O O OH HO O OH HO HO H HO H N N 4 3 O O O OH O COOH OH O OOO O O OH HO O O OH HO HO H N HO H CH OH N 2 NH O 5 6 O OH OH O O COOH COOH O O HO O OH HO O OH H HO H F N N S 7 O N 8 O H OH OH O O COOH COOH O O OH HO O OH HO O NH H O H HO N N S N O 9 O 10 H HO 640 Anti-Cancer Agents in Medicinal Chemistry, 2008, Vol. 8, No. 6 Pande et al. (Fig. 1) contd…. OH OH O O COOCH COOH 2 HO O HO O O OH HO O OH HO 11 12 HO O OH O O F O O CH3 O HO HN O OH HO H N N HO H N NH O N H 14 O 13 O O OH O O O HO HO H N HO H N O N H O N H 16 15 O OH O O HO H O N CH3 O N H 17 Fig. (1). Chemical structures of balanol (1) and some of its analogs. Fig. (2). Three-dimensional stick representations of (a) balanol and (b) adenosine triphosphate (ATP), as found in their respective complexes with PKA (PDB ids.: 1BX6 and 1ATP, respectively). Carbon atoms are colored in green, oxygens in red, nitrogens in blue and phosphorus atoms in yellow. The Protein Kinase Inhibitor Balanol Anti-Cancer Agents in Medicinal Chemistry, 2008, Vol. 8, No. 6 641 physical properties resulting in better cellular activity and bioavail- balanol, but a number of analogs were identified with improved ability. Here, we discuss the SAR studies reported based on various isozyme selectivity. The SAR studies on these molecules also indi- substructure modifications in the balanol molecule. Just two years cated that (i) for optimal general PKC inhibition a free 4-hydroxyl after its discovery, that is, in 1995 [41], a variety of related mole- group in the benzamido portion of the molecule was required, (ii) cules bearing either a carboxylic acid (present in the benzophenone the amide linkage of the benzamido moiety is important for PKC moiety) or several replacements (amides, sulfonamides, and tetra- inhibition, and (iii) the conformation associated with the benzamido zoles) were synthesized and evaluated for PKC inhibitory activity. moiety appears to have a profound effect on PKC inhibition. It was thought that an important feature of the benzophenone region In another series [48], the carboxamide linkage between the p- of the molecule was the carboxylate moiety and, in fact, when the hydroxybenzamide and perhydroazepine moieties was shortened to carboxylic acid was replaced by a simple proton or a hydroxyl a single atom bridging unit. This study concluded that balanol ana- group, the PKC inhibitory activity dramatically decreased. None- logs containing a cyclopentane skeleton and a methylene spacer in theless, while this acidic functionality appeared to be necessary for place of the carboxamide moiety were potent inhibitors of PKC enzyme inhibition, its polar nature was thought to limit cell perme- isozymes and displayed excellent selectivity for PKC over PKA.
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