Protein Kinase Inhibitors
Current Pharmaceutical Design, 2012, Vol. 18, No. 20
2851
Editorial Protein Kinase Inhibitors: Current Strategies and Future Prospects Protein kinases (PKs) play key roles in signal transduction pathways. Therefore, aberrant PK activity can cause significant alterations in many important cellular processes such as transcription, proliferation, differentiation, angiogenesis, and inhibition of apoptosis, thereby contributing to a variety of illnesses including cancer, metabolic disorders, inflammation, autoimmune diseases, diabetes, etc [1]. More than 1000 X-ray crystal structures indicate that all PKs share certain structural similarities, comprising a small N-terminal lobe and a larger Cterminal lobe, with a highly conserved catalytic domain. ATP adjusts perfectly in a cleft between the lobes, and the protein substrate binds at the entrance of the cleft. PKs catalyze the transfer of the terminal -phosphate of the ATP to the hydroxyl group on the side chains of tyrosine, serine, or threonine residues of the substrate proteins. Phosphorylation results in a conformational change in the structure in many enzymes and receptors, causing them to become activated or deactivated. The discovery of PK inhibitors has attracted growing interest for novel drugs research and development [2]. The success of smallmolecule such as imatinib, nilotinib, and dasatinib for the treatment of chronic myelogenous leukemia, sunitinib and sorafenib for the treatment of renal cell carcinoma, gefitinib and erlotinib for the treatment of non-small-cell lung cancer, and lapatinib for the treatment of breast cancer and other solid tumours, confirm that ATP-competitive inhibitors are effective [3-5]. The discovery of ATP-competitive PK inhibitors has increased exponentially in the last years. Emerging knowledge of the both structure and the mechanism of action and modulation of PKs provided clues for the development of the new inhibition strategies. The design of ATP-competitive PK inhibitors faces a challenging selectivity problem because of the high structural homology between the ATP-binding site of PKs. Therefore, some novel strategies have been identified to explote other functionally critical binding sites. These approaches include substrate competitive inhibitors and targeting of allosteric sites that stabilize inactive conformations, and non-catalytic domains [6]. In general, the majority of reported PK inhibitors are low-molecular-weight organic compounds. However, other species have been explored and several findings suggest that new strategies will be developed in the future. For instance, inert metal coordination species have been identified as potent PK inhibitors, demonstrating that metal complexes can provide a powerful tool for the design of novel innovative drugs [7]. Other example are dual binding or bivalent PK inhibitors which are able to bind two distinct sites on a protein, enhancing selectivity for the targeted PK [8]. In this issue focusing on PK inhibitors, we outline some of the most interesting topics in this area. Some strategies and investigations related to the design of PK inhibitors are presented. International experts have made the state of the art in some ATP-competitive inhibitors of several recognized targets. In addition, application of PK inhibitors in the development of small molecule radiotracers to image PKs is presented [9]. The use of structural data and computational methods in the design of new PK inhibitors and the establishment of design rules that contribute to the rational design and selectivity of PK inhibitors was also revised [10]. This issue also provides reviews on novel strategies such as the use of inhibitor bioconjugates oriented to increase drug accumulation at the designated pathological tissue and decrease off-organ toxicities [11], constrained peptides as PK inhibitors [12], and bivalent PK inhibitors [13]. In conclusion, we envisage that the papers in this issue will contribute to help researchers to learn from the vast structural data on PKs and explore new methods for PK inhibitors discovery. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Matthews DJ, Gerritsen ME. Targeting Protein Kinases for Cancer Therapy. John Wiley &Sons Inc. Hoboken: New Jersey 2010. Li R, Stafford JA. Kinase Inhibitor Drugs. Li, R., Stafford, JA (Eds)., John Wiley & Sons, Hoboken New Jersey 2009. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov, 2006; 5: 835-44. Garland P, Apperley J. Nilotinib: evaluation and analysis of its role in chronic myeloid leukemia. Future Oncol, 2011; 7: 201-18. Wei G, Rafiyath S, Liu D. First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. J Hematol Oncol, 2010; 3: 47. Bogoyevitch MA, Fairlie DP. A new paradigm for protein kinase inhibition: blocking phosphorylation without directly targeting ATP binding. Drug Discov Today, 2007; 12: 622-33. Kunick C, Ott I. Metal complexes as protein kinase inhibitors. Angew Chem Int Ed Engl, 2010; 49: 5226-7. Harmsen S, Dolman ME, Nemes Z, Lacombe M, Szokol B, Pato J, Keri G, Orfi L, Storm G, Hennink WE, Kok RJ. Development of a cell-selective and intrinsically active multikinase inhibitor bioconjugate. Bioconjug Chem, 2011; 22: 540-5. Kniess T. Radiolabeled small molecule inhibitors of VEGFR – recent advances. Curr Pharm Des 2012; 18(20): 2867-74. Caballero J, Alzate-Morales JH. Molecular dynamics of protein kinase–inhibitor complexes: a valid structural information. Curr Pharm Des 2012; 18(20): 2946-63. Harmsen S, Kok RJ. Kinase Inhibitor Conjugates. Curr Pharm Des 2012; 18(20): 2891-2900. Tiwari RK, Parang K. Conformationally Constrained Peptides as Protein Tyrosine Kinase Inhibitors. Curr Pharm Des 2012; 18(20): 2852-66. Lamba V, Ghosh I. New Directions in Targeting Protein Kinases: Focusing Upon True Allosteric and Bivalent Inhibitors. Curr Pharm Des 2012; 18(20): 2936-45.
Julio Caballero Assistant Professor, Facultad de Ingeniería en Bioinformática Centro de Bioinformática y Simulación Molecular, Universidad de Talca, Talca, Chile
E-mail:
[email protected] or
[email protected]