Introduction: The kinase super family

In recent years the broadening of technology has enabled researchers to investigate the role of ligands in relation to cellular responses. To achieve understanding the binding properties, conformation changes, receptor response and protein binding domains similarity have been extensively researched, most notably in the field of oncology. The protein kinases are not really a new discovery but the relationship between proteins is now beginning to be understood. Over 500 different distinct proteins exist under the super family heading of protein kinases. These proteins govern the growth, proliferation, differentiation and apoptosis of nearly all aspects of the mammalian system. The protein kinase family is subdivided into small related protein series that seem to work together to receive a signal from an extracellular source and translated this into cellular activity. One of the sub-families receiving a substantial amount of interest is the tyrosine kinase receptor family. This family of proteins recruits and phosphorylates other proteins in a related series that pass a response from the cell membrane to the nucleus triggering cellular activity. This activity is ADP dependant and a specific domain exists in the protein structure where the phosphorylation is performed. Research has identified, mapped and modeled this domain so that molecules can be designed by computer simulation to bind either reversible or irreversible to this domain. The result was one of the most notable events in oncology in recent years, Imatinib [1-5].

This molecule was determined to perform inhibition of the tyrosine kinase in vitro and in vivo to a significant degree [6]. Considering that in oncology the formation of tumors is based on the uncontrolled growth of cells, the inhibition of a tyrosine kinase pathway would interfere with the cellular growth and gene transcription. The Imatinib mechanism of action performed this task on the Abl pathway in mammalian cells. It was not the only pathway inhibited (additionally cKit and PDGFR) but was considered the most important for this drug. The Imatinib Abl inhibitor was quickly recognized as a huge success but only in a subset of patients with over expressing disease involving the BcR- Abl fusion protein. As a result of quickly conducted phase I and II trials imatinib was introduced into the clinic reaching approved drug status relatively quickly.

Imatinib: Properties and availability

With the formulation name “Gleevec” Imatinib is one of the most commercially successful tyrosine kinase inhibitors on the market. For a year’s course of treatment (21 days on; 7 days off) the cost for each patient with CML range from $32,000 for children to $98,000 for adults. The Imatinib price for a year’s supply of the 100 mg tablet costs $9600 to make based on Novartis released manufacturing data. The discrepancy between the two costs has generated anger among health care professionals who feel that desperate dying patients are being taken advantage off. The Imatinib structure is based on the core mole 2-phenylaminopyrimidine with an ortho methyl substitution which increases its potency. However, the structure is not suitable for dissolution in aqueous media even at low pH; hence Imatinib is mostly supplied as the maleate salt which is soluble at pH’s below 5.5. For cell culture Imatinib solubility DMSO up to a maximum concentration of 25 mg/ml. Activity for Imatinib has been found for PDGFR (A&B); CSF-1R; NTRK1, RET, ABL1 (BCL-ABL fusion) and c-KIT; activity has also been observed for a host of smaller targets as well confirming Imatinib is a pan – kinase inhibitor. Imatinib IC50 ranges from low nM up to 100nM for the least sensitive of its targets. Imatinib suppliers make it possible to buy Imatinib at reasonable costs (range $38 – 395 for 500 mg) and Imatinib stability is such that if stored at -20°C the retesting date can be 2 years.

Imatinib: Clinical Status

At Phase I Imatinib has been tested in a variety of solid and advanced tumors demonstrating a clear benefit in patients with the BCR-Abl fusion protein and the Philadelphia chromosome, After success of trials in GIST, myeloid leukemia, ALL and CML [7-13] Imatinib was moved to phase II. At Phase II Imatinib treatment was restricted to relapsed or refractory Ph(+) ALL patients who carry the BCR-Abl fusion protein where 60-90 % success was observed . Also phase II tested out Thyroid, pancreatic, prostate and breast cancers but results indicated the molecule was ineffectual in these conditions [14-21]. At the Phase III level Imatinib was tested on GIST, colorectal, CML and AML [22-25]. As a direct result of the phase III trials gleevac received FDA approval for first line use in GIST [26;27]





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