KINASE INHIBITORS TARGETTING CANCER ABERRATIONS

Tyrosine kinases: Mechanisms and inhibition

The super families of protein kinases are found extensively in mammalian tissues, they regulate most of the proliferation, differentiation, migration, apoptosis, motility and gene transcription that occurs in the life span of natural cell. One of the sub families is that of the tyrosine kinases (TK’s) which exist in a variety of forms, each triggering a signaling cascade which performs specific cellular functions [1] The mechanism of action TK’s is the direct phosphorylation of tyrosine amino acid in the binding domain of a protein. This action triggers an event to occur passing down a signaling cascade to effect cellular functions [2]. TK’s can be subdivided into two families the non receptor tyrosine kinase (nrTK) and the receptor tyrosine kinase (rTK). The numbers of members in each family are 32 and 58 respectively; the rTK has been subdivided again into 20 different groups [3]. The TK’s are involved in processes that are of considerable interest in the field of the prevention of cancer. The blocking cellular growth or the induction of apoptotic processes constitute then focus of nearly all cancer chemotherapy. In addition research has demonstrate that certain TK’s can be mutated so that they exist in a state permanent activity thereby inducing cancerous growth [1;4-9] Tyrosine kinase inhibition with kinase inhibitor drugs is the focus of a significant proportion of the research currently being undertaken. Significant success has been achieved by targeting the tyrosine kinase receptors with tyrosine kinase pathway inhibitors. In a brief tyrosine kinase inhibitors review focusing on those that are registered for clinical treatment many of the pharmacokinetic factors can be found

 

Tyrosine kinases under development:

Small molecule tyrosine kinase inhibitors are a growing field of research with upwards of 50 different small molecules being independently investigated. It is impractical to give a complete list of all the molecules under investigation since new members of tyrosine kinase selective inhibitors are being introduced or discarded every year [10-15]. A proportion of these small molecules are tyrosine kinase specific but others inhibit a broad range of targets. Those that are proving most successful in the clinic tend to be the multiple kinase inhibitors. Each tyrosine kinase antagonists or tyrosine kinase agonists can be classified into groups which target different TK pathways. Anti-Tyrosine kinase activity for each molecule can vary according its structure and the more sensitive it is the less toxicity seems to occur. It is recommended to buy tyrosine kinase inhibitors with great care, prices can vary between $40-50 per 10 mg up to $1500 per 10 mg for the same compound of the same purity.

Clinic Therapeutics of tyrosine kinases

Of the receptor tyrosine kinase inhibitors under development 12 have been approved (as of 2012) by the FDA and 10 by the EMA for clinical use. The first molecule to be approved was Imatinib for use in Acute Lymphoblastic leukemia (ALL) and chronic myelogenous leukemia (CML) [16-18]. Subsequently Gefitinib was approved for use in NSCLC [19-21], next on the list is Erlotinib which has been approved for NSCLC and pancreatic cancer [22-24]. Further approved molecules are Sorafenib (Renal cell carcinoma (RCC)), Desatinib (CML and ALL), Sunitinib (RCC, pancreatic and GIST), Nilotinib (CML). Additional there is Lapatinib a tyrosine kinase inhibitors, breast cancer,  Pazopanib (RCC), Vandetanib (Thyroid), Vemurafanib (Melanoma), Critozinib (NSCLC) and finally Ruxolitinib (Myelofibrosis).

Tyrosine kinase inhibitors in clinical trials at this moment that demonstrate significant results include Foretinib, Dovitinib, Tofacitinib and Tandutinib. While others small molecules have failed in phase III trials, eg. Bosutinib, Lestauretinib, Mubritinib and Vatalanib. Outside of cancer the spleen tyrosine kinase inhibitor R788 is currently being tested in Rheumatoid arthritis [25].

References

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   3.   Robinson DR, Wu YM et al. The protein tyrosine kinase family of the human genome. Oncogene 2000; 19(49):5548-5557.

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10.   Koc G, Wang X et al. Pazopanib: an orally administered multi-targeted tyrosine kinase Inhibitor for locally advanced or metastatic renal cell carcinoma. Can J Urol 2011; 18(6):5991-5997.

11.   Hudkins RL, Becknell NC et al. Synthesis and Biological Profile of the pan-Vascular Endothelial Growth Factor Receptor/Tyrosine Kinase with Immunoglobulin and Epidermal Growth Factor-Like Homology Domains 2 (VEGF-R/TIE-2) Inhibitor 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-inda zolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): A Novel Oncology Therapeutic Agent. J Med Chem 2012.

12.   Lim J, Taoka B et al. Discovery of 1-amino-5H-pyrido[4,3-b]indol-4-carboxamide inhibitors of Janus kinase 2 (JAK2) for the treatment of myeloproliferative disorders. J Med Chem 2011; 54(20):7334-7349.

13.   Guagnano V, Furet P et al. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phe nylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem 2011; 54(20):7066-7083.

14.   Ott GR, Wells GJ et al. 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazines: new variant of an old template and application to the discovery of anaplastic lymphoma kinase (ALK) inhibitors with in vivo antitumor activity. J Med Chem 2011; 54(18):6328-6341.

15.   Ohshima Y, Hanaoka H et al. Preparation and biological evaluation of 3-[(76)Br]bromo-alpha-methyl-L-tyrosine, a novel tyrosine analog for positron emission tomography imaging of tumors. Nucl Med Biol 2011; 38(6):857-865.

16.   Lyseng-Williamson K, Jarvis B. Imatinib. Drugs 2001; 61(12):1765-1774.

17.   Dagher R, Cohen M et al. Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 2002; 8(10):3034-3038.

18.   Marin D, Marktel S et al. The use of imatinib (STI571) in chronic myelod leukemia: some practical considerations. Haematologica 2002; 87(9):979-988.

19.   Cohen MH, Williams GA et al. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 2003; 8(4):303-306.

20.   Dyer O. FDA announces fast track approval of new drug for lung cancer. BMJ 2003; 326(7397):1004.

21.   Prommer E. Gefitinib: a new agent in palliative care. Am J Hosp Palliat Care 2004; 21(3):222-227.

22.   Cohen MH, Johnson JR et al. FDA drug approval summary: erlotinib (Tarceva) tablets. Oncologist 2005; 10(7):461-466.

23.   Johnson JR, Cohen M et al. Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res 2005; 11(18):6414-6421.

24.   Minna JD, Dowell J. Erlotinib hydrochloride. Nat Rev Drug Discov 2005; Suppl:S14-S15.

25.   Weinblatt ME, Kavanaugh A et al. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med 2010; 363(14):1303-1312.