Author: Stevens, Kirk L.

Source: Current Topics in Medicinal Chemistry, Volume 7, Number 17, September 2007 , pp. 1753-1753(1)

Publisher: Bentham Science Publishers

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.

Document Type: Research article

DOI: http://dx.doi.org/10.2174/156802607782341000

Affiliations: 1: Oncology Medicinal Chemistry GlaxoSmithKline R&D 5 Moore Dr, 3.4174-4B, Research Triangle Park, NC 27709 USA.

Publication date: 2007-09-01

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