DASATINIB- A MULTI ACTION INHIBITOR

by Selleckchem | Apr 15 2012

Cancer has always been an area of research that has got much attention due to its diversity in reasons and mechanisms and hence to look for the treatment. Metastasis is another challenge that has to be controlled over in order to get rid of this disease completely. Due to this diversity every single treatment does not necessarily suits every single cancer patient. Therefore it is need of the hour to discover and synthesize new and more effective drugs with lesser toxicity as occurs in different chemotherapeutic agents for example in case of leukemia, Imatinib is a very good example. Toxicity of Imatinib at high level led the scientists to discover a new drug named Dasatinib. Dasatinib BMS-354825 is comparatively efficient and is less toxic. It is sold under the trade name of Sprycel. Dasatinib has been named on the name of the inventor Jagabandhu Das and was developed by Squibb [1].

PROPERTIES OF DASATINIB
Dasatinib is a small molecule that is active against two different types of RTKs and hence is used for treating a lot of cancer types. Dasatinib has been designed to inhibit Src, bcr, abl and many different kinds of tyrosine kinases. It is available in the form of a vial of 500 mg and one can buy Dasatinib in 50 dollars. Dasatinib is insoluble in water or ethanol and is soluble in DMSO upto the extent of 200mg/ml. Dasatinib SRC inhibitor is administered orally to the patient. Dasatinib IC50 for SRC and ABL tyrosine kinase enzymes is 0.55 nM and 3 nM respectively [2]. As Dasatinib is involved in multi kinase inhibition, it is a very famous drug for treating cancers of different types and is being used against (CML) chronic myeloma leukemia and (Ph+ ALL) acute lymphoblastic leukemia Philadelphia positive [3-5] especially after the development of resistance in them against imatinib.

MECHANISM OF ACTION OF DASATINIB
Dasatinib has a varying degree of specificity and hence has the property of inhibition against different types of molecules. The macromolecules against which this inhibitor shows activity include BCR, ABL, SRC and c-Kit. Comparative study with imatinib has shown it to be efficient upto 300 times [6]. Similarly the cell lines showing resistance to imatinib has also been shown to get affected by Dasatinib ABL inhibitor having a specific structure is able to react as Dasatinib BCR-ABL inhibitor with respective macromolecule in different forms [7]. Dasatinib has the ability to bind the cell lines disregarding of the mutation in them. In CML culture system, Dasatinib showed to inhibit CrKL phosphorylation [1]. Dasatinib has also found to be efficient against prostate cancer as it was observed to block Src kinases, Lyn, SFKs and also down regulated p130CAS signaling [8]. Another dimension in the activity of Dasatinib is the efficiency of it against non-small cell lung carcinoma (NSCLC) and head and neck cancer [9].

CLINICAL TRIALS OF DASATINIB
In prior pre-clinical studies, this dual kinase inhibitor is very efficient against triple negative cell lines of breast cancer i.e., the cell lines without progesterone, estrogen and HER2 [10]. CML patients showing resistance against imatinib gave a good hematological response, In spite of having quite tolerable side effects, in large number of patients when studied in the clinical trial in phase I [11]. Similarly high efficiency with lower toxicity has been studied in the same imatinib resistant patients in clinical trial phase III [3, 12]. The drug has proved effective in Philadelphia positive patients of ALL [13]. Dasatinib, in clinical trial phase II, has shown to have lesser toxicity and no metastasis [14]. The price of Dasatinib and as compared to its function is quite reasonable and attractive for the doctors to recommend.

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.

Cat.No.	Product Name	Information
S1021	Dasatinib	Dasatinib is a novel, potent and multi-targeted inhibitor that targets Abl, Src and c-Kit, with IC50 of <1 nM, 0.8 nM and 79 nM in cell-free assays, respectively. Dasatinib induces autophagy and apoptosis with anti-tumor activity.
S1026	Imatinib Mesylate	Imatinib Mesylate is an orally bioavailability mesylate salt of Imatinib, which is a multi-target inhibitor of v-Abl, c-Kit and PDGFR with IC50 of 0.6 μM, 0.1 μM and 0.1 μM in cell-free or cell-based assays, respectively. Imatinib Mesylate (STI571) induces autophagy.