Structural Basis of Src Tyrosine Kinase Inhibition with a New Class of Potent and Selective Trisubstituted Purine-based Compounds (original) (raw)
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Design Strategies, Structures and Molecular Interactions of Small Molecule Src Inhibitors
Anti-Cancer Agents in Medicinal Chemistry, 2016
In recent years, several small molecules approved by FDA for clinical studies are promising anti-cancer agent. Among the kinases, Abelson Leukaemia (Abl), sarcoma (Src), epidermal growth factor receptor (EGFR) and vascular endotelhial growth factor receptor (VEGFR) are considered as primary molecular targets for selective inhibition and the best successful targeted therapy of tyrosine kinase inhibitors (TKIs) has been achieved in the treatment of Bcr (break point cluster)-Abl leukemia. The majority of type 1 kinase inhibitors target the active conformation of ATP binding site. In consequence of intensive studies on kinases, type 2, type 3 (allosteric) and type 4 (covalent) inhibitors have been discovered beyond the type 1 inhibitors. Although the selectivity is a major problem for type 1 inhibitors, these new type of inhibitors are promising for finding new selective compounds, which may provide other therapeutic options for cancer therapy. They may also be a solution to overcome drug resistance that remains unresolved yet. Threedimensional structural determination provides the development of specific and highly binding properties of compounds. Studying the prediction of a binding mode of inhibitors, homology model developments from kinaseligand co-crystal structures and isosteric replacements have been used to improve binding properties of inhibitors. In this review, critical results related to the design strategies of kinase specifically targeted to Src and Bcr-Abl kinases and therapeutic potential of novel inhibitors will be evaluated. The readers will be endowed with the functional role of Src and Bcr-Abl kinases that lead inhibitor design, the structural analysis of binding modes of kinase inhibitors, the current progress in terms of therapeutic interventions and the mission of leading groups in the field.
Structural basis for selective inhibition of Src family kinases by PP1
Chemistry & Biology, 1999
Small-molecule inhibitors that can target individual kinases are powerful tools for use in signal transduction research. It is difficult to find such compounds because of the enormous number of protein kinases and the highly conserved nature of their catalytic domains. Recently, a novel, potent, Src family selective tyrosine kinase inhibitor was reported (PPl). Here, we study the structural basis for this inhibitor's specificity for Src family kinases.
Current Advances in the Development of Anticancer Drugs Targeting Tyrosine Kinases of the Src Family
Current Drug Therapy, 2008
Protein kinases, either membrane-embedded receptorial or cytosolic non-receptorial ones, are important transducers of cell proliferation signals. In almost all tumor cells, the activity of some kinases is deregulated, either because of the presence of cancer-specific aberrant forms, or as a consequence of alterations in regulatory pathways, at the transcriptional or post-transcriptional level, which increase the activity of protein kinases with respect to normal cells. The study of the non-receptor tyrosine kinase Src plays a pivotal role in the field of the molecular genetics of cancer. The Src family of kinases (SFKs) comprises nine members, Src, Fyn, Yes, which are expressed in most tissues, and Blk,Yrk, Fgr, Hck, Lck and Lyn, which are more selectively expressed in particular tissues. To date, cellular (c-) Src has been implicated in the development of human cancer. Like oncogenic v-Src, activated mutants of c-Src can transform cells in culture and induce tumours in chickens. In addition, Src protein expression and/or activity is elevated in epithelial cancers, or cell lines derived from these, and there is often an association with advancement of disease or with malignancy. During the past decade, examples of tyrosine kinases inhibitors have been reported. Many of these compounds were highly active in vitro, but only a few demonstrated in vivo activity. These approaches led to the characterization of the PP1/PP2 derivatives as very strong and selective inhibitors of the c-Src family of kinases. Unfortunately, attempts to improve the biological profile of the latter compounds have so far met little success. Following these studies, some other inhibitors, possessing different chemical structures and interesting c-Src inhibitory activity, have been recently reported. Some of these molecules showed potent inhibition of tumor cell proliferation, which was due to the interference with the signalling pathway at the level of Src tyrosine kinase, providing proof-of-principle for the targeting of Src in anticancer chemotherapy.
Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor
Nature Structural Biology, 2002
Iterative structure-based design was used to optimize the ATPcompetitive inhibition of CDK1 and CDK2 by O 6 -cyclohexylmethylguanines, resulting in O 6 -cyclohexylmethyl-2-(4′sulfamoylanilino)purine. The new inhibitor is 1,000-fold more potent than the parent compound (K i values for CDK1 = 9 nM and CDK2 = 6 nM versus 5,000 nM and 12,000 nM, respectively, for O 6 -cyclohexylmethylguanine). The increased potency arises primarily from the formation of two additional hydrogen bonds between the inhibitor and Asp 86 of CDK2, which facilitate optimum hydrophobic packing of the anilino group with the specificity surface of CDK2. Cellular studies with O 6 -cyclohexylmethyl-2-(4′sulfamoylanilino) purine demonstrated inhibition of MCF-7 cell growth and target protein phosphorylation, consistent with CDK1 and CDK2 inhibition. The work represents the first successful iterative synthesis of a potent CDK inhibitor based on the structure of fully activated CDK2-cyclin A. Furthermore, the potency of O 6 -cyclohexylmethyl-2-(4′-sulfamoylanilino)purine was both predicted and fully rationalized on the basis of protein-ligand interactions.
Chemical Biology & Drug Design, 2008
Targeted disruption of the pp60(src) (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Here, we describe structure activity relationships of a novel series of carbon-linked, 2-substituted purines that led to the identification of AP23451 as a potent inhibitor of Src tyrosine kinase with antiresorptive activity in vivo. AP23451 features the use of an arylphosphinylmethylphosphinic acid moiety which confers bone-targeting properties to the molecule, thereby increasing local concentrations of the inhibitor to actively resorbing osteoclasts at the bone interface. AP23451 exhibited an IC50 = 68 nm against Src kinase; an X-ray crystal structure of the molecule complexed with Src detailed the molecular interactions responsible for its Src inhibition. In vivo, AP23451 demonstrated a dose-dependent decrease in PTH-induced hypercalcemia. Moreover, AP23517, a structurally and biochemically similar molecule with comparable activity (IC50 = 73 nm) except devoid of the bone-targeting element, demonstrated significantly reduced in vivo efficacy, suggesting that Src activity was necessary but not sufficient for in vivo activity in this series of compounds.
Bioorganic & Medicinal Chemistry Letters, 2003
Novel bone-targeted 2,6,9-trisubstituted purine template-based inhibitors of Src tyrosine kinase are described. Drug design studies of known purine compounds revealed that both positions-2 and -6 were suitable for incorporating bone-seeking moieties. A variety of bone-targeting groups with different affinity to hydroxyapatite were utilized in the study. Compound 3d was determined to be a potent Src inhibitor and was quite selective against a panel of other protein kinases. #
Journal of Medicinal Chemistry, 2005
Screening of a directed compound library in a yeast-based assay identified 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (2a) as a Src inhibitor. An enzymatic assay established that 2a was an ATP-competitive inhibitor of the kinase activity of Src. We present here SAR data for 2a which shows that the aniline group at C-4, the carbonitrile group at C-3, and the alkoxy groups at C-6 and C-7 of the quinoline are crucial for optimal activity. Increasing the size of the C-2 substituent of the aniline at C-4 of 2a from chloro to bromo to iodo resulted in a corresponding increase in Src inhibition. Furthermore, replacement of the 7-methoxy group of 2a with various 3-heteroalkylaminopropoxy groups provided increased inhibition of both Src enzymatic and cellular activity. Compound 25, which contains a 3-morpholinopropoxy group, had an IC 50 of 3.8 nM in the Src enzymatic assay and an IC 50 of 940 nM for the inhibition of Src-dependent cell proliferation.