Tyrosine Kinase Blockers: New Hope for Successful Cancer Therapy

Abstract

Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment.

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

“…Briefly, synergism or antagonism for CLM3 plus SN-38 was calculated on the basis of a multiple drug-effect equation, and quantitated by the CI where CI<1, CI=1, and CI>1 indicates synergism, additive effect, and antagonism, respectively. Based on the classic isobologram for mutually exclusive effects, the CI value was calculated as: 2 are the concentrations of CLM3 and SN-38 in combination that also inhibits cell growth by 50% (isoeffective as compared with the single drugs alone). The dose-reduction index (DRI) defined the degree of dose reduction that is possible in a combination for a given degree of effect as compared with the concentration of each drug alone:…”

“…Understanding the mechanisms of normal and aberrant tyrosine kinase signalling and strategies to inhibit them in angiogenesis and cancer, further promote the development of novel agents [1,2].…”

ENMD-2076 Is an Orally Active Kinase Inhibitor with Antiangiogenic and Antiproliferative Mechanisms of Action

“…This class of agents is used both in combination regimens and as single agents (1)(2)(3). However, it has become evident that resistance mechanisms such as host mutations quickly render highly specific therapeutic agents ineffective (4).…”

Genome-wide shRNA screen reveals increased mitochondrial dependence upon mTORC2 addiction

“…This expectation has been partially fulfilled, particularly for oncoproteins with protein kinase activity, which allowed the development of targeted inhibitors with substantial clinical benefit (Thaimattam et al, 2007;Muller, 2009;Pytel et al, 2009). Conversely, clinical translation of efforts focused on currently 'non-druggable' oncoproteins, such as transcription factors or G-proteins, have been disappointing and any future progress will depend on further breakthroughs.…”