DASATINIB; A Receptor Tyrosine Kinase inhibitor

by Selleckchem | Jun 25 2012

PROPERTIES OF DASATINIB
Researchers and scientists are trying hard to find a better drug with good efficiency because cancer has become the cause of huge deaths all over the world and secondly resistance to the available drugs in cancer cells is increased. Cancer cells evade the action of particular medicine to become resistant by mutating themselves in a number of ways. Metastasis is also another problem related to cancer. For chemotherapy of cancer cell toxicity adds to the problem. To combat these afore mentioned difficulties it is necessary as well as mandatory to devise new medicines. Imatinib was given for years but due to its toxicity and other effects mentioned above it forced scientists to develop a less toxic and more efficient medicine. So in this regard Jagabandhu Das developed a new medicine called Dasatinib. Dasatinib BMS 354825 got very popular as compared to Imatinib because of its lesser toxicity and more efficiency.It is developed by a pharmaceutical company Squibb and marketed under the trade name of Sprycel [1].
Dasatinib behaves as anti-RTKs which mean it inhibits tyrosine kinase receptors. It is a small molecule that costs around 50$ for 500mg of packaging and anyone can buy Dasatinib from Dasatinib supplier. Low Dasatinib price favors its buying. Dasatinib solubility is 200mg/ml of DMSO while it is insoluble in water and ethanol. Dasatinib SRC inhibitor is administered orally. For ABL and SRC tyrosine kinases, Dasatinib IC50 is 3 nM and 0.55 respectively [2].

DASATINIB MODE OF ACTION
Dasatinib inhibits different kinds of tyrosine kinase receptors which favored it to be used for treatment of various cancers. In pre-clinical trials Dasatinib was given to patients who have resistance for Imatinib and were having chronic myelogenous leukemia (CML) and were having acute lymphocytic leukemia (ALL) with Ph+, very positive results related to its efficiency were obtained [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 also shown more effective results [7]. As compared to Imatinib, Dasatinib attaches more specifically with cancer cells. Mechanism of action of Dasatinib was studied in CML cultures and more efficient inhibitory action was seen against CrKL phosphorylation [1]. Dasatinib was found to inhibit a lot of signaling cascades for example Src kinases, Lyn, p130CAS and SFKs in prostate cancer [8]. In another study related to Dasatinib action it was found that it inhibits proliferation of cells when given to cell lines of NSCLC and HNCC or head neck cancer [9].

CLINICAL TRIALS STUDY OF DASATINIB
Due to the absence of HER2, progesterone and estrogen it is hard to carry out in vitro studies in breast cancer cell lines. In some preclinical studies done on triple negative breast cancer cell lines have shown efficient results [10]. In phase I clinical trials excellent response was shown by majority of CML patients having resistance to Imatinib [11] with few manageable and tolerable side effects. It proved less-toxic and efficient in phase II Dasatinib clinical trial on patients having acute lymphoblastic leukemia with Ph+ [12]. Similar proved Dasatinib has less toxicity and zero progression in tumor growth in patients of CML [13]. In clinical trials Phase III it showed outstanding results on Imatinib resistant CML patients [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.