DASATINIB- A DRUG OF CHOICE

by Selleckchem | Jun 04 2012

INTRODUCTION
Diverse types of cellular systems are there in human bodies that differ structurally and functionally from one another. Each cellular system is controlled by a variety of controllers called cell cycle regulatory proteins. Defective controllers may lead to abnormal cellular systems and the condition known as cancer may develop. Cancer may be of different types depending upon the defect in the cell cycle regulatory proteins. Cancer may also vary on the basis of stage of the defective condition. Many therapies have been devised in order to treat cancerous cells. Further research is also being done for developing better, more specific and less toxic therapies and to cope with the development of resistance in the defective cells against existing therapies. Besides resistance, metastasis is also another issue to be resolved in case of cancerous cells. Imatinib has been used against leukemia for several years but due to high levels of toxicity scientists discovered a new drug, called Dasatinib, for the same therapy. Dasatinib BMS-354825 is more efficient and less toxic as compared to Imatinib. The drug is being marketed by the name of Sprycel. As Dasatinib was discovered by Jagabandhu Das, it was named Dasatinib. Development of the drug was done by Squibb Company [1].

PROPERTIES OF THE DRUG
Dasatinib inhibits different types of tyrosine kinases including Src, abl and bcr, therefore it is used for many different types of cancers. Researchers or doctors can buy Dasatinib 500 mg vial in 50 $. A soluble solution of 200 mg/ml of Dasatinib can be made in DMSO while it is insoluble in ethanol or water. It is an orally administered drug and Dasatinib IC50 for inhibition of ABL and SRC tyrosine kinases is 3 nM and 0.55 nM respectively [2]. Dasatinib is being used for the treatment of a variety of cancers most prominently after the patients had developed resistance against imatinib e.g., Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloma leukemia (CML) [3-5].

MODE OF ACTION
The specificity of Dasatinib is quite variable; therefore it is able to inhibit different molecules like ABL, BCR, c-Kit and SRC. When the efficiency of Dasatinib is compared with imatinib, it was found to be 300 times more active [6]. Imatinib resistant cell lines have shown that Dasatinib ABL inhibitor can also act as Dasatinib BCR-ABL inhibitor [7]. It can bind any type of cell line irrespective of the mutation that they have. It inhibits the phosphorylation of CrKL in the culture system of CML [1]. Dasatinib has been seen to inhibit Src kinase, SFKs, Lyn. It has also been seen to downregulate p130CAS hence is found to be effective for prostate cancer [8]. The drug has also been found active against head and neck cancer and (NSCLC) non-small cell lung carcinoma [9].

DASATINIB IN CLINICS
Dasatinib was studied against breast cancer cell lines that were triple negative i.e., without progesterone, HER2 and estrogen. The drug proved efficiency against it [10]. Imatinib resistant CML patients gave good hematological response, although most of the patients developed some side effects which were quite tolerable in clinical trial of phase I [11]. In similar patients high efficiency and low toxicity is observed in the phase III clinical trial [3, 12]. Dasatinib has shown efficiency against the patients of acute lymphoblastic leukemia who were Philadelphia positive [13]. Other characteristics of the drug that have been discovered in phase II Dasatinib clinical trial are that it is less toxic and no metastasis has been observed [14]. Due to these properties and successful clinical trials, Dasatinib is a very attractive drug for cancer treatment.

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. 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.
13. 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.
14. 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.