Download PDF
The Translation Post Vol.1 Issue1
Review Article - Kinases in Cancer
By Herve Le Calvez, Ph.D., Director Business Development |
|
|
|
Kinases in Cancer
The kinase family is one of the largest target families in the human genome. Together, it is estimated that there are more than 500 members of the major classes of protein serine/threonine, tyrosine, and dual specificity kinases within the human genome [1, 2]. Protein phosphorylation is one of the most significant signal transduction mechanisms by which intercellular signals regulate crucial intracellular processes such as ion transport, cellular proliferation, and hormone responses. Consistent with the complex role of this post-translational modification in the cell, protein kinases can be regulated by activator proteins, inhibitor proteins, ligand binding to regulatory subunits, cofactors, and phosphorylation by other proteins or by themselves (autophosphorylation). For discovering reversible protein phosphorylation as a biological regulatory mechanism, Edmond H. Fischer and Edwin G. Krebs were awarded the 1992 Nobel Prize for Physiology and Medicine. The familys key function in signal transduction for all organisms makes it a very attractive target class for therapeutic interventions in many disease states such as cancer, diabetes, inflammation, and arthritis. In this regard, protein kinases represent as much as thirty percent of all protein targets under investigation by pharmaceutical companies. Recent successful launches of drugs with kinase inhibition as the mode of action demonstrate the ability to deliver kinase inhibitors as drugs with the appropriate selectivity, potency, and pharmacokinetic properties [3, 4]. The latest reports of cancer treatment using kinase inhibitors are reviewed in this article.
Tyrosine Kinases: a major target
Targeting receptor protein tyrosine kinases (RPTKs) as a cancer chemotherapy has continued to become a compelling approach with time. Preclinical and clinical data strongly support the involvement of specific RPTKs in the formation and progression of a subset of solid and liquid tumors. The advances in our understanding of the oncogenic activation of these receptors have been matched by the identification of new structural classes of kinase inhibitors with improved potency, specificity and efficacy [5]. Subsequently, half of the kinase inhibitors about 65 total - currently in clinical trials are targeting RPTKs.
STI-571 (Imatinib/Gleevec, Novartis) is a highly successful cancer drug due to its activity as an inhibitor of the Abelson cytoplasmic tyrosine kinase (Abl), which is constitutively active in a majority of patients with chronic myelogenous leukemia (FDA-approved in May 2001). STI-571 also inhibits two type III receptor tyrosine kinases, c-Kit and platelet-derived growth factor receptor (PDGFR), and functions by targeting inactive conformations of these kinases. SU11248 (Pfizer) is an oral medication with anti-tumor and anti-angiogenic activity. As a cancer therapeutic, SU11248 blocks the molecular signals generated by certain tyrosine kinases: PDGFR, VEGFR, KIT, and FLT3. Signals from these tyrosine kinases promote the development and sustain the growth of some cancers. SU11248 is an experimental drug not yet approved by the FDA. Numerous Phase I, II & III clinical trials are under investigation for gastrointestinal stromal, colorectal and metastatic breast cancer treatments. Embracing a similar approach of broader inhibition spectrum, Exelixis has developed the XL999 inhibitor by using their Spectrum Selective Kinase Inhibitor technology platform (SSKI). Each inhibitor developed with SSKI has a different spectrum of RPTK inhibition offering the potential to achieve efficacy through inhibition of multiple RPTKs based on their established or potential involvement in cancer. In pre-clinical testing, XL999 inhibited KDR, FGFR1, PDGFR-beta and FLT3 with high potency. In animal models, XL999 exhibited a broad spectrum of antitumor activity across several tumor types and shrinkage of large, well-established xenografts. Further evaluation in phase I trials have been started in 2004 for XL999 as well as other kinase inhibitors discovered by using SSKI.
ZD6474 (Astra Zeneca) is a potent inhibitor of VEGFR2 tyrosine kinase activity. This compound has some additional activity versus the tyrosine kinase activity of fms-like tyrosine kinase 4 (VEGFR3) and epidermal growth factor receptor (EGFR/HER1) and yet demonstrates selectivity against a range of other tyrosine and serine-threonine kinases. Although less promising than ZD1839, ZD6474 is currently evaluated alone or in combination with other drugs in Phase I & II clinical trials for non-small cell lung cancer (NSCLC) and thyroid cancer treatments. The epidermal growth factor receptor (EGFR/ErbB2) tyrosine kinase signal transduction pathway has an important role in cell proliferation, motility, adhesion, invasion, survival, and angiogenesis. Dysregulation of this pathway contributes to the development and progression of malignancies. ErbB1 or ErbB2 receptor expression or over-expression has been observed in pediatric high grade gliomas, medulloblastomas, ependymomas, osteosarcomas, neuroblastoma, and rhabdomyosarcoma. ZD1839 (gefitinib/Iressa, Astra Zeneca) is the first drug approved by FDA (May 2003) for advanced NSCLC that targets EGFR. ZD1839 is currently evaluated alone or in combination with other drugs in numerous clinical trials for colorectal, neck, prostate, ovarian and breast cancer treatments. IMC-C225 (cetuximab/Erbitux, ImClone Systems) and trastuzumab (Herceptin, Genentech) are two monoclonal antibodies directed against EGFR and HER-2 that received FDA approval in May 2004 and September 1998 for colorectal and breast cancer treatments respectively. OSI-774 (erlotinib/Tarceva, OSI Pharmaceuticals) is an orally bioavailable epidermal growth factor (EGFR/ErbB2) receptor tyrosine kinase inhibitor that has received FDA approval for advanced NSCLC in November 2004. OSI-774 is still currently evaluated alone or in combination with other drugs in numerous Phase I, II & III clinical trials for brain, pancreas, neck and breast cancer treatments. Lapatinib ditosylate (GSK572016) is an EGFR)
|
|
|
and ErbB-2 (Her2/neu) dual tyrosine kinase inhibitor under development by GlaxoSmithKline as a treatment for breast and lung cancer. This novel investigational agent has attracted considerable interest, as it appears to arrest the development of breast cancer in some patients with metastatic, treatment-refractory disease. If preliminary findings are supported by data from larger phase III trials then lapatinib could become an important new treatment option for breast cancer patients and potentially those with other difficult-to-treat solid tumours. Originally, GSK had hoped to file for regulatory approval of lapatinib in 2004 but this has now been extended to 2005 to allow more time for completion of clinical trials.
Besides RPTKs, other tyrosine kinases are targeted for cancer treatments: Ras/Raf inhibitors for solid tumors are in Phase I & II, Src/Lck inhibitors for bone metastasis are in Pre-IND, and a TrKA inhibitor for prostate cancer is in Phase II. |
Serine-Threonine Kinases: strong candidates on the rise
Although tyrosine kinase inhibitors are the most evaluated kinase inhibitors in clinical trials, a third of kinase inhibitors are targeted against Ser/Thr kinases that belong to the AGC kinase family containing PKA, PKG, PKC kinase families.
Aurora kinases play a role in cell cycle regulation during anaphase and telophase in relation to the function of the centrosome/spindle pole region during chromosome segregation. Aurora kinases are implicated in the onset and progression of many different human cancers by disregulating phosphorylation of histone H3 and the tumor suppressor p53. Preclinical results for VX-680 (Vertex Pharmaceuticals) reported in early 2004 demonstrated for the first time that a compound targeting the Aurora mechanism could induce tumor regression in human models of solid tumor cancers. A phase I study has been started for treatment of leukemia and pancreatic cancer. AZD1152 (AstraZeneca), another Aurora kinase inhibitor for solid tumors will be evaluated in patient trials in 2005. The small-molecule drug, AP23573 (Ariad Pharmaceuticals), starves cancer cells and shrinks tumors by inhibiting the critical cell-signaling protein, mTOR, which regulates the response of tumor cells to nutrients and growth factors, and controls tumor blood supply and angiogenesis through effects on VEGF. Sustained anti-tumor activity of AP23573 was demonstrated as a single agent in two phase I clinical trials in patients with a broad spectrum of advanced, refractory and/or metastatic solid tumors. These initial results were obtained in patients with lung, kidney, bone, thyroid, liver and soft tissue cancers. Other compounds, rapamycin and analogs, are in phase I, II & III as immunosuppressors acting on mTOR pathway. Perifosine (Aeterna Laboratories and Keryx Biopharmaceuticals) is the prototype of a new group of anti-cancer drugs referred to as alkylphosphocholines that appear to be potent inhibitors of the activation of Akt, a protein associated with tumor survival and growth. Akt is activated in approximately 10-50% of most tumor types and in most anti-cancer therapies, thus involves in resistance to treatment. Once activated, Akt promotes cell survival and cell proliferation.
|
|
Several phase I & II trials have been started in cancer patients refractory to prior chemotherapy. Inhibitors of protein kinase-C (PKC) isoforms are in different phases of evaluation. ISIS 3521 (LY900003/Affinitak, Isis Pharmaceuticals and Eli Lilly) is an antisense drug that blocks production of PKC-alpha studied in patients with NSCLC. PKC412 (Novartis) is an inhibitor of multiple signaling proteins. PKC412 may impact several targets involved in cell growth (KIT, PDGFR, PKC), leukemic cell proliferation (FLT3), and angiogenesis (VEGFR2). In preclinical studies, PKC412 showed broad antiproliferative activity against various tumor cell lines, including those that were resistant to several other chemotherapeutic agents. Orally administered PKC412 is currently being tested in phase II clinical studies in patients with various cancers.
|
Other kinase targets that belong to the CMGC (containing CDK, MAPK, GSK3, CLK) and STE (homologs of yeast Sterile 7, Sterile 11, Sterile 20) kinase families are studied for drug discovery. The cyclin-dependent kinases (CDK) by their pivotal role in cell cycle are heavily investigated. HMR-1275 (Flavopirodol, Aventis) is an inhibitor of CDK4 evaluated in phase III in patients with NSCLC. CYC202 (R-roscovitine/Seliciclib, Cyclacel) is evaluated in phase I & II for patients with leukemia, breast, colon, or lung cancers. BMS-387032
|
|
(Bristol-Myers Squibb) is an inhibitor of CDK2 evaluated in a phase I trial for solid tumors. Inhibitors of MEK1/2 have been developed by Astra Zeneca/Array BioPharma (AZD6244/ARRY-142886), Pfizer (PD-184352) and Merck (U-0126). They are evaluated in phase I & II trials for different cancers, including melanoma, pancreatic, colon, lung and breast cancers. MEK is a critical enzyme at the intersection of several biological pathways, which regulates cell proliferation, survival, migration and differentiation as part of the ras/raf/MEK/erk pathway.
|
How many other kinase targets opened for exploration?
To capture the impact of protein kinases within the cell, consider that approximately one third of mammalian proteins contain covalently bound phosphate. Disruption of protein kinase function or regulation is implicated in a host of major diseases, such as cancer, diabetes and rheumatoid arthritis. Defects in genes that encode protein kinases underlie a number of inherited and acquired disorders, which include leukemias, lymphomas and autoimmune diseases. Even with the enormous amount of research and clinical success with the likes of inhibitors for protein kinase mTOR (for immunosuppression for organ transplantation) Abelson tyrosine kinase and c-Kit receptor tyrosine kinase (chronic myelogenous leukemia and gastrointestinal stromal tumors), and the EGF receptor tyrosine kinase (non-small cell lung cancer), the overwhelming majority of kinases remain largely uncharacterized.
Pictures
Antigen models were built using the alignment algorithm FFAS 03. The peptide sequence used as antigen to raise the specific kinase antibody is labeled as epitope in yellow.
References
1. Blume-Jensen, P. and T. Hunter, Oncogenic kinase signalling. Nature, 2001. 411(6835): p. 355-65.
2. Manning, G., et al., The protein kinase complement of the human genome. Science, 2002. 298(5600): p. 1912-34.
3. Cohen, P., Protein kinases--the major drug targets of the twenty-first century? Nat Rev Drug Discov, 2002. 1(4): p. 309-15.
4. Vieth, M., et al., Kinomics-structural biology and chemogenomics of kinase inhibitors and targets. Biochim Biophys Acta, 2004. 1697(1-2): p. 243-57.
5. Garcia-Echeverria, C. and D. Fabbro, Therapeutically targeted anticancer agents: inhibitors of receptor tyrosine kinases. Mini Rev Med Chem, 2004. 4(3): p. 273-83.
Other sources of information:
http://www.clinicaltrials.gov
http://sev.prnewswire.com
|
