Kinase Inhibitor-Based Cancer Drugs

Communication among and within cells involves in a series of signaling cascade. In the normal cells, the communication is balanced. The cancerous transformation of a cell often results from an excess of certain antennae-like receptors that reside on the cell membrane and protrude into the cell's interior. Activation of these receptors can initiate a cascade of biochemical signals that effectively tell the cell to proliferate wildly and then promote survival of the resulting tumor. Protein kinases play critical role in the signaling pathways. It is possible to use kinase inhibitor to suppress kinase activity and to control tumor growth.

Table 6. Kinase Inhibitor-Based Cancer Drugs

Gleevec (Imatinib mesylate) is the first kinase inhibitor approved for treatment of cancer, chronic myelonic leukemia (CML). In CML, there is a constant signal that tells the body to keep producing abnormal white blood cells. The constant signal is created by three events: first, there is a change in a person's DNA; second, this change forms the Philadelphia (Ph) chromosome (named after the city where it was discovered), third, the Ph chromosome creates an abnormal protein that tells the body to send out the constant signal. Gleevec is a tyrosine kinase inhibitor and works by interfering with the abnormal protein, Bcr-Abl, and blocking it from telling the body to keep making more and more abnormal white blood cells. It is a therapy that affects the molecular cause of CML.

Like Gleevec, Sprycel (Dasatinib, BMS354825) is also a kinase inhibitor. But Sprycel is 300 to 1000 times more potent than Gleevec for inhibition of Bcr-Abl tyrosine kinase. Dasatinib is also an Src inhibitor as well as an Abl inhibitor. It is orally bio-available and can be taken as an oral pill. Nilotinib represents the next generation targeted, oral therapy specifically designed to be the most selective inhibitor of Bcr-Abl.

AZD0350 is an Src kinase inhibitor with capacity of reducing tumor invasion and of preventing tumors from spreading.

EKB-569, Iressa, and Tarceva are kinase inhibitors that target epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor (HER1), which is critical to cell growth in many cancers. EGFR/HER1 is a key component of the HER signaling pathway, which is often involved in the formation and growth of numerous cancers. These kinase inhibitors are designed to inhibit specifically the kinase activity of HER1/EGFR, thereby blocking the signaling pathway with the intent of potentially inhibiting tumor cell growth.

CEP-7055, PTK787, and ZD6474 are vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. Angiogenesis, the natural process used by the human body to produce blood vessels, occurs as a pathological process in the development of solid tumors. The blood vessels created by this process provide the nutrients and oxygen the tumor needs to grow and spread. The process of angiogenesis is mediated by a number of factors including polypeptide VEGF. As a result, inhibitors of the receptor kinase for VEGF have potential utility in the treatment of solid tumors. ZD6474 also has activity against epidermal growth factor receptor tyrosine kinase.

MLN518 is a small molecule specifically designed to inhibit the fms-like tyrosine kinase-3 (FLT-3) receptor tyrosine kinase in patients with acute myeloid leukemia (AML).

Perifosine is an alkyphosphocholine with structural similarity to phospholipids that are main constituents of cellular membranes. It targets AKT/protein kinase B activity and exerts cytotoxic effect.

PKC412 is a kinase inhibitor that blocks several isoforms of protein kinase C (PKC) and receptors for VEGF, platelet-derived growth factor, and stem cell factor, inhibits vascularization.

Nexavar is an orally active, small molecule agent. It targets the RAF kinase, receptors of vascular endothelial growth factor and platelet-derived growth factor. This novel compound inhibits both tumor cell proliferation and angiogenesis.

VX-680 represents the first drug to stop tumors by targeting enzymes called Aurora kinases.  Aurora kinases play an important role in mitosis, or the process of cell division, which is out of control in cancer patients. Aurora kinases have been identified as overly abundant in certain types of cancer, such as leukemia, colon cancer and breast cancer. MLN8054 is a novel small molecule inhibitor of Aurora kinase(s) and exhibits potent anti-tumor activity against a variety of human tumor xenograft models.

Tykerb, Lipatinib, is an ErbB-1 (EGFR) and ErbB-2 (HER-2/neu) dual kinase inhibitors. These two receptors have been implicated in the growth of various tumor types, and often are associated with a poor prognosis.

Sutent is an oral small molecule drug that inhibits several kinases. These are enzymes needed for cell functions.  The specific enzymes that Sutent inhibits are the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), Kit (a transmembrane receptor tyrosine kinase), and FLT3 receptor tyrosine kinases. By inhibiting these enzymes these receptors have their function inhibited. The drug has anti-angiogenic effects because VEGF and PDGF are important to many types of tumor to develop new blood supplies that are needed for tumor growth. VEGF and PDGF have been implicated in the growth of melanoma tumors.  It also has direct anti-tumor effects.

Enzastaurin HCl (LY317615, e-HCl), an acyclic bisindolylmaleimide, is a potent inhibitor of Protein Kinase C-beta isozyme. The beta isoform lies in the signal cascade of VEGF and inhibition of this pathway may lead to a block in tumor angiogenesis.

AMG 706 is a potent, oral, multi kinase inhibitor with anti-angiogenic and anti-tumor activity achieved by selectively targeting all known VEGF, PDGF, Kit and Ret receptors.

CEP-701 is a class of small, orally active molecules that are selective inhibitors of tyrosine kinase, thus, antagonizing the "survival" signal elicited by this receptor and inhibiting tumor growth.