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DASATINIB – THE DOUBLE-EDGED SWORD

by Selleckchem | Mar 13 2012

Introduction: BCR-ABL and SCR targets

Researchers are continuously searching for the magic compound which will cure all diseases but most know that this is a physical impossibility. Every disease is different and especially cancers where even tumors of the same site / type can be radically different. In CML, AML and ALL a mutation in two chromosomes has been linked to the onset of these diseases in a proportion of patients [1]. The defect is referred to as the “Philadelphia chromosome”, here a section of chromosome 9 and chromosome 22 have swapped places (translocated) [2]. The end result is that chromosome 9 is longer than it should be while chromosome 22 is shorter than it should be. The significance of this change is that the coding for the BCR gene and the ABL gene become mixed up (fused). The protein from this genetic fusion is referred to as the BCR-ABL fusion protein. Studies have shown that this protein is related to the protein kinase super family and has serine / threonine kinase activity, it also has phosphorylation activity for the cytoskeletal enzyme p21 Rac (Cdc42) [3]. Imatinib is a small molecule inhibitor of the ABL in Chronic Myeloid Leukemia, Acute Myeloid Leukemia and Acute Lymphoblast Leukemia tumors that has been proven very successful in the clinic. However, patients with the translocated gene demonstrate resistance to Imatinib due in part to the nature of fused BCR-ABL gene [4]. In an effort to overcome this resistance a molecule similar to Imatinib was designed and screened for activity against this fusion protein. This molecule demonstrated highly significant activity against the desired target and was quickly carried through into clinical testing.

Dasatinib (BMS-354825) Chemical Structure

Dasatinib: Properties and availability

The DASATINIB Aurora inhibitor is marketed by the Bristol-Meyers Squibb company under the trade name of Sprycel but originally it was researched with the drug code BMS-354825. The DASATINIB structure is based on a tri substituted pyrimidine ring. DASATINIB solubility in water and ethanol is extremely poor but DASATINIB is soluble in DMSO at a maximum concentration of 200 mg/ml. DASATINIB stability is listed for its powdered free base and this can be stored for upwards of 2 years if kept at -20^oC or below. Researchers can buy DASATINIB free base from a variety of DASATINIB suppliers although DASATINIB cost is dependent on the supplier. DASATINIB price of a 1 g vial can range from $83 up to $1600; researchers are advised to shop very carefully for this product.

Dasatinib: Preclinical investigations

One of the theories concerning Imatinib resistance was the elevated expression of SCR and the loss of function due to the “Philadelphia chromosome” in BCR and ABL proteins. Dasatinib was therefore originally designed as a specific inhibitor for the BCR-ABL fusion protein and SCR [5], subsequently it has demonstrated significant activity in this regard (Dasatinib IC50 SCR – 0.55 nM; ABL – 3 nM, BCR – 3nM for purified protein) [6].The design was successful and Dasatinib mechanism of action demonstrates efficacy of approximately 300 times more compared to Imatinib [7]. Dasatinib has also shown activity towards a multitude of other tyrosine kinases including c-KIT and the ephrin receptors. The Dasatinib ABL inhibitor has demonstrated effective inhibition of nearly all the BCR-ABL mutations, the exception being T3151 mutation. This ability is linked to the nature of the Dasatinib structure in relation to the tyrosine binding domain [8]. In addition to Dasatinib SRC inhibitor action on CML,AML and ALL it has been investigated in neoplastic eosinophils [9], prostate cancer [10-12], GIST [8] and gastrointestinal stromal tumors[13]. Preclinically Dastinib has demostrated consistent activity and potency marking it for fast track approval. The success of Dasatinib clinical trials at phase II and III led to Dasatinib being approved in 2006 for the Oral tablet treatment of CML [14;15]. In clinical trials for other tumor types the typical reports seen are “poorly tolerated”, limited efficacy and “failed to meet expectations” [16-28]. These conclusions indicate that Dasatinib while potent in vitro has significant pharmacokinetic or pharmacodynamic problems in the human system at doses needed for effective treatments. Much research needs to be done to address this issue.

References

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