Molecule of the Month

Kirk   L.   Stevens

Abstract

Approaching a magic bullet? Less than a decade ago, the Food and Drug Administration (FDA) approved the first kinase inhibitor, Gleevec ™ , for chronic myelogenous leukemia (CML) and later for gastrointestinal stromal tumors (GIST). Gleevec, acting on the bcrabl oncogene, was hailed as a magic bullet due to its perceived selectivity profile as a targeted therapy agent versus traditional chemotherapy [1]. Since the landmark 2001 approval of Gleevec ™ [2], seven more kinase inhibitors have been added to the anti-cancer arsenal. These include Sutent ™ for renal cell carcinoma (RCC) and GIST [3], Nexavar ™ also for RCC [4], Iressa ™ for non-smallcell lung cancer (NSCLC) [5], Tarceva ™ for NSCLC and pancreatic cancer [6], Torisel ™ for RCC [7], and Sprycel ™ for CML [8]. In March, the FDA approved Tykerb ™ , the first small molecule kinase inhibitor indicated for the treatment of breast cancer [9]. Tykerb ™ treatment is indicated in combination with Xeloda ™ , for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress Her-2 (also called ErbB2) and who have received prior therapy with taxanes, anthracycline, and Herceptin ™ . Her-2 is responsible for stimulating tumor cell growth, found in excessive amounts in about 30% of primary breast cancers, and generally indicates poor prognosis. The Erb family proteins are well-precedented targets in oncology therapy with two commercial monoclonal antibodies (Herceptin ™ and Erbitux ™ ) on the market. Herceptin ™ , is the front-line therapy for breast cancer in women whose tumors overexpress the Her-2 gene [10]. Erbitux ™ targets inhibition of EGFR (also called ErbB1) and is indicated for the treatment of colorectal and head and neck cancers [11]. Tykerb ™ targets both of these key proteins involved in cancer. Whereas Herceptin ™ targets Her-2 through a cell surface receptor, the small molecule Tykerb ™ can enter the cell to inhibit the intracellular kinase domain. This difference in mechanism of inhibition may explain why Tykerb ™ works in some Her-2 positive breast cancer patients that are no longer benefiting from Herceptin ™ treatment [12]. Unlike other approved kinase inhibitors, Tykerb ™ and Gleevec ™ bind to an “inactive-like” kinase conformation [13]. Binding to “inactive-like” kinase conformations may provide some advantages for blocking biological activity through mechanisms related to the overall signal transduction process. In addition, Tykerb ™ has a very slow off-rate from the purified intracellular domains of EGFR and ErbB2 compared with other Erb family kinase inhibitors [14]. The slow off-rate, inactive-like binding, and dual ErbB1/ErbB2 inhibition may provide Tykerb ™ an attractive efficacy profile. Despite the abundance of recent approvals, the 600 registered clinical trials of kinase inhibitors for use in cancer (www.clinical trials.gov), and the many success stories, further research is needed to maximize the value of these therapies since no magic bullet has been uncovered for this complex area [15]. REFERENCES [1] Verweij, J.; Judson, I.; van Oosterom, A. STI571: a magic bullet? Eur. J. Cancer 2001, 37, 1816-1819. [2] a) FDA approves Gleevec for leukemia treatment FDA consumer 2001, 35(4), 6. b) Dagher, R.; Cohen, M.; Williams, G.; Rothmann, M.; Gobburu, J.; Robbie, G.; Rahman, A.; Chen, G.; Staten, A.; Griebel, D.; Pazdur, R. Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin. Cancer Res. 2002, 8(10), 3034-3038. [3] Rock, E.; Goodman, V.; Jiang, J.; Mahjoob, K.; Verbois, S.; Morse, D.; Dagher, R.; Justice, R.; Pazdur, R. Food and drug administration drug approval summary: sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. Oncologist 2007, 12(1), 107-113. [4] Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R.; Schwartz, B.; Simantov, R.; Kelley, S. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat. Rev. Drug Discov. 2006, 5(10), 835-844. [5] Vansteenkiste, J. Gefitinib (Iressa): a novel treatment for non-small cell lung cancer. Expert Rev. Anticancer Ther. 2004, 4(1), 5-17. [6] Johnson, J.; Cohen, M.; Sridhara, R.; Chen, Y.; Williams, G.; Duan, J.; Gobburu, J.; Booth, B.; Benson, K.; Leighton, J.; Hsieh, L.; Chidambaram, N.; Zimmerman, P.; Pazdur, R. 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. [7] http://www.fda.gov/- search Torisel. [8] Shah, N. Dasatinib. Drugs Today 2007, 43(1), 5-12. [9] a) Glaxo Reports Approval by the F.D.A. of a Drug for Breast Cancer’ New York Times, Online Edition, March 14th, 2007. b) Moy, B.; Kirkpatrick, P.; Kar, S.; Goss, P. Lapatinib. Nat. Rev. Drug Discov. 2007, 6(6), 431-432. c) Lackey, K. Lessons learned from the drug discovery of lapitinib, a dual ErbB1/2 tyrosine kinase inhibitor. Curr. Topics Med. Chem. 2006, 6, 435- 460. [10] Herceptin ™ had 2006 US sales of US$1.2 billion. For more information see: http://www.gene.com/gene/ir/financials/historical/herceptin.jsp [11] Erbitux ™ had global sales of US$306 million in the first quarter of 2007. For more information see: http://www.imclone.com/index.php - click to investor relations. [12] Moy, B., Goss P. Lapatinib: Current Status and Future Directions in Breast Cancer. Oncologist 2006, 11 (10), 1047-1057. [13] Schindler T., Bornmann W., Pellicena P., Miller W., Clarkson B., Kuriyan J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000, 289, 1938 – 42. [14] Wood, E.; Truesdale, A.; McDonald, O.; Yuan, D.; Hassell, A.; Dickerson, S.; Ellis, B.; Pennisi, C.; Horne, E.; Lackey, K.; Alligood, K.; Rusnak, D.; Gilmer, T.; Shewchuk, L. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004, 64(18), 6652-6659. [15] a) Maitland, M.; Ratain, M. Terminal ballistics of kinase inhibitors: there are no magic bullets. Ann. Int. Med. 2006, 145(9), 702-703. b) Frantz, S. Iressa failure raises fears about accelerated approvals. Nat. Rev. Drug Discov. 2005, 4(2), 94-95. c) Dancey, J.; Freidlin, B. Targeting epidermal growth factor receptor - are we missing the mark? Lancet 2003, 362(9377), 62-64.

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