DASATINIB; AN ANTI-RTK DRUG

by Selleckchem | May 16 2012

DASATINIB AND ITS PROPERTIES
The high rate of deaths due to cancer and the development of resistance in the cancerous cells for existing drugs are encouraging the scientists and researchers to look for more efficient drugs. Occurrence of different types of mutations makes the cancerous cells to evade the drugs’ action against them. Metastasis is another problem in cancer that complicates the issue. Toxicity is another that is raised in cancer chemotherapy, therefore considering all of the developing complexities, new drugs are quite necessary to be discovered and developed. In case of leukemia, Imatinib had been used since long but due to the complexities associated with this drug, as mentioned above, led the scientists to look for another less toxic and more efficient drug. Jagabandhu Das was the discoverer of a drug in this regards i.e., Dasatinib named so after its discoverer. Dasatinib BMS 354825 got very popular because of lesser toxicity and more efficacies as compared to that of imatinib. It was developed by the company Squibb and is sold under the name of Sprycel [1].
Dasatinib is an anti-RTKs i.e., it inhibits receptor tyrosine kinases. It is a small molecule and is available in a packing of 500 mg and scientists or researchers can buy Dasatinib around 50 $. Dasatinib price is quite reasonable that makes it easier to buy. Dasatinib solubility in DMSO can be achieved upto 200 mg/ml while it is insoluble ethanol and water both. Dasatinib SRC inhibitor is administered orally. For ABL and SRC tyrosine kinases, Dasatinib IC50 is 3 nM and 0.55 respectively [2].

MECHANISM OF ACTION OF THE DRUG
Dasatinib is being used for treating cancers of many types owing to its ability to inhibit multiple types of RTKs. It has given efficient results against CML and Ph+ ALL patients in pre-clinical trials both which were resistance against imatinib [3-5]. This drug has shown 300 times more efficiency in in vitro models as compared to imatinib. Dasatinib BCR-ABL inhibitor shows a varying degree of inhibition for different types of kinases e.g., different specificities have been observed for Src family e.g., Eph kinases, c-Kit, Src etc. [6]. Dasatinib Src inhibitor has been studied against different types of BCR-ABL and observe to have more efficient results as compared to imatinib [7]. Dasatinib binds more efficiently to the imatinib resistant cancerous cells irrespective of the mutation type that they have. In a study regarding mechanism of action of Dasatinib done cultures of CML, Dasatinib has been found to have inhibitory action against CrKL phosphorylation [1]. The effect of Dasatinib has also been studied for the case of prostate cancer in humans by employing its property to inhibit Src kinases, SFKs and Lyn and p130CAS signaling pathway by down regulating it [8]. Another dimension to the mechanism of action of the drug has been given to the drug after studies on NSCLC (non small cell lung cancer) cell lines and on head and neck cancer in which Dasatinib has been seen arrest the cell cycle [9].

CLINICAL TRIALS
In vitro studies of the breast cancer cell lines are difficult due to the absence of progesterone, HER2 and estrogen. In some preclinical studies done on triple negative breast cancer cell lines have shown efficient results [10]. Imatinib resistant CML patients when studied in clinical trial phase I showed complete hematological response in large number of patients [11] but with some side effects which were tolerable and manageable. Dasatinib clinical trial in phase II was done in Ph+ ALL patients and was proved to be safe and effective [12]. Similar studies in CML patients proved the drug to have lesser toxicity and least or zero progression [13]. For CML patients Dasatinib has also been studied in clinical trial phase III proving it to be more efficient and less toxic in imatinib resistant CML patients [3, 14].

REFERENCES:
1. Copland, M.e.a., Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood, 2006. 107: p. 4532-4539.
2. Lombardo, L.J.e.a., Discovery of N-(2-chloro-6-methylphneyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in pre-clinical assays. J. Med. Chem., 2004. 47: p. 6658-6661.
3. Hochhaus, A.e.a., Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood, 2007. 109(6): p. 2303-2309.
4. Cortes, J.e.a., Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood, 2007. 109: p. 3207-3213.
5. Guilhot, F.e.a., Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood, 2007. 109: p. 4143-4150.
6. O’Hare, T.e.a., In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib resistant Abl kinase domain mutants. . Cancer Res, 2005. 65: p. 4500-4505.
7. Tokarski, J.S.e.a., The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants. Cancer Res, 2006. 66(11): p. 5790-7.
8. Nam, S.e.a., Action of the Src Family Kinase Inhibitor, Dasatinib (BMS-354825), on Human Prostate Cancer Cells. Cancer Res, 2005. 65: p. 9185.
9. Johnson, F.M.e.a., Dasatinib (BMS-354825) Tyrosine Kinase Inhibitor Suppresses Invasion and Induces Cell Cycle Arrest and Apoptosis of Head and Neck Squamous Cell Carcinoma and Non-Small Cell Lung Cancer Cells. Clin Cancer Res, 2005. 11: p. 6924.
10. Finn, R.S.e.a., Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro. Breast Cancer Research and Treatment, 2007. 105(3): p. 319-326.
11. Talpaz, M.e.a., Dasatinib in Imatinib-resistant Philadelphia chromosome-positive leukemias. N. Engl. J. Med., 2006. 354(24): p. 2531-41.
12. Ottmann, O.e.a., Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood, 2007. 110(7): p. 2309-2315.
13. Kantarjian, H.e.a., Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood, 2007. 109(12): p. 5143-5150.
14. Shah, N.P.e.a., Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia. Journal of Clinical Oncology, 2008. 26(19): p. 3204-3212.