DASATINIB; An inhibitor of Receptor Tyrosine Kinase

The amplified death rate because of cancer and multidrug resistance development in cancer cells for existing drugs are the persuasive force for the researchers as well as scientists to explore new drugs that have better efficiency. Each cellular system is organized by a diversity of controllers called cell cycle regulatory proteins.Cancer cells have the capability to mutate themselves in a variety of ways which make them to detour the action of a specific drug. Another concern with the cancer is that it metastasizes. Other difficulty with the chemotherapy of cancerous cells is toxicity. So considering afore mentioned problems it is evident and compulsory to search for new drugs. Due to above mentioned problematic effects of Imatinib which has been administered for years induces scientists to search for a more mild and more active drug. In this matter a new drug called Dasatinib was discovered by Jagabandhu Das. In contrast to Imatinib, Dasatinib BMS 354825 became renowned due to its lesser harmful and more efficient nature. This drug was discovered by Squibb Company and it is sold as Sprycel [1].
Dasatinib is an inhibitor of tyrosine kinases receptors so it acts as anti-RTKs. Packet of 500mg of this tiny molecule costs approximately 50 $ and it is offered to either  researchers or scientists who want to buy Dasatinib. The inexpensive Dasatinib price makes it easier for consumer to buy it. 200mg/ml of dimethyl sulfoxide (DMSO) is appropriate for Dasatinib solubility since it istotally insoluble in ethanol and water. The drug that is orally administered is Dasatinib SRC inhibitor. The structural investigation revealed that Dasatinib IC50 for SRC tyrosine kinase receptors and ABL it is 0.55 and 3nm respectively [2].

The capability of Dasatinib to block several types of receptor tyrosine kinases has made it aencouraging choice to treat different types of cancer. The pre-clinical trials consisted of patients who were unaffected to Imatinib treatment and affected from chronic myelogenous leukemia and Ph+ acute lymphocytic leukemia gave very productive results about the effectiveness of drug [3-5]. The efficacy evaluation of the drug in vitro proved far enhanced than Imatinib drug. Dasatinib BCR-ABL inhibitor also has been seen to inhibit various sorts of RTKs at different intensities for example for Src family (c-Kit, eph kinases, Src) was seen to be inhibited at different specificities [6]. In contrast to Imatinib, Dasatinib Src inhibitor also has verified to be more active [7]. Even Dasatinib attaches to the mutant cancer cells more precisely in comparison with Imatinib. In anassessment study related to Dasatinib’s mode of action in CML cultures it was discovered that it is most effective CrKL phosphorylation inhibitor [1]. To study the effectiveness of Dasatinib in prostate cancer it has shown to block a number of signaling pathways such as SFKs, Src kinases, Lyn and p130CAS by stopping them [8]. Other property of Dasatinib was assessed in NSCLC cell lines and in HNNC (head neck cancer) where it was observed to stop the growth cycle of cell [9].

It is challenging to study in vitro the cell lines of breast cancer because of the deficiency of estrogen, HER2 and progesterone. Preclinical studies conducted on cancer cell lines of breast cancer of triple negative type showed promising results [10]. Clinical trials of phase I comprised of CML patients resilient to Imatinib stated a very good reaction by majority of the patients [11] however rareneglect able and adjustable side effects were observed. Dasatinib clinical trial of phase II proved harmless and competent in Ph+ acute lymphoblastic leukemia patients [12]. Associated studies exhibited that it is much less toxic and has zero tumor progress in CML patients [13]. In case of chronic myelogenous leukemia patients the drug has been considered for phase III clinical trials showed very encouraging results in CML patients resistant to Imatinib [3, 14].

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.


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