Protein kinases as drug targets in cancer.
Identification of the key roles of protein kinases in signaling pathways leading to development of cancer has caused pharmacological interest to concentrate extensively on targeted therapies as a more specific and effective way for blockade of cancer progression. This review will mainly focus on inhibitors targeting these key components of cellular signaling by employing a technology-based point of view with respect to ATP- and non-ATP-competitive small molecule inhibitors and monoclonal antibodies of selected protein kinases, particularly, mammalian target of rapamycin (mTOR), BCR-ABL, MEK, p38 MAPK, EGFR PDGFR, VEGFR, HER2 and Raf. Inhibitors of the heat shock protein Hsp90 are also included in a separate section, as this protein plays an essential role for the maturation/proper activation of cancer-related protein kinases. In the following review, the molecular details of the mode of action of these inhibitors as well as the emergence of drug resistance encountered in several cases are discussed in light of the structural, molecular and clinical studies conducted so far.
Arslan
Mehmet Alper
MA
Biological Sciences and Bioengineering Program, Sabanci University, Orhanli-Tuzla 34956, Istanbul, Turkey.
Kutuk
Ozgur
O
Basaga
Huveyda
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001549:Benzamides / Q000494:pharmacology; D001557:Benzenesulfonates / Q000627:therapeutic use; D000077156:Gefitinib; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D015398:Signal Transduction; D020123:Sirolimus / Q000627:therapeutic use; D000077157:Sorafenib; D000068878:Trastuzumab; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001549:Benzamides; D001557:Benzenesulfonates; D018841:HSP90 Heat-Shock Proteins; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D048051:p38 Mitogen-Activated Protein Kinases; D000068878:Trastuzumab; D000077156:Gefitinib; D020123:Sirolimus