Cytoskeletal Pharmacopeia

Courtesy of Cytokinetics Ovarian cancer cell line OVCAR3 fixed and stained with fluorescent markers against nuclei, Golgi apparatus, microtubules, and actin. The panels represent the same image color combined in different combinations to highlight different organizational patterns. Founded in 1998, Cytokinetics of South San Francisco, Calif., specializes in discovering, developing, and commercializing small-molecule therapeutic agents that target cytoskeletal proteins. Although the subspecialty arena of cytoskeletal pharmaceuticals might seem fairly narrow at first glance, the potential benefits of this approach are far-reaching. Cytoskeletal components play fundamental roles in a range of cellular processes, including celldivision, motility, intracellular transport, and muscle contraction, and they have been implicated in a wide range of pathological conditions, including cancers, cardiovascular diseases, and neurological disorders. From the outset, Cytokinetics' overall strategy has been to codevelop pharmaceutical research tools and information technologies that work together cohesively to facilitate drug discovery and development. In the few years since its inception, this young company has not only developed integrated platforms for high-througput screening (HTS) and secondary screening, but also has established an infrastructure for compound handling and data management. Cytokinetics first identifies promising bioactive compound hits in primary screenings against small-compound libraries. These primary screens employ the company's PUMA™ HTS system, which supports a variety of application-specific, multiprotein biochemical assays that mimic biological function, and are geared towards identifying agents that target any of a variety of cytoskeletal proteins under study. Promising compounds are then more thoroughly profiled in secondary screens employing the company's Cytometrix™ technologies for automated and quantitative cellular phenotyping. "Cytometrix cellular phenotyping technologies enable Cytokinetics' scientists to quickly analyze a compound's influence on a wide range of cellular functions that give rise to both on-target and off- target biological effects," says David J. Morgans Jr., Cytogenetics' senior vice president of drug discovery. "This approach efficiently focuses our lead selection, analoging, and lead optimization efforts to produce and advance extremely high-quality compounds." Due to intellectual property concerns, the company is unwilling to provide specific details regarding its PUMA and Cytometrix technologies at this time. But, the potential import of results obtained using these technologies is no secret. Cytokinetics' interest in mitotic kinesins has already led to the discovery of a candidate chemotherapeutic agent in collaboration with pharmaceutical giant GlaxoSmithKline. CYTOCHEMOTHERAPY Interference with mitotic spindle function is a well-established chemotherapeutic strategy.1 Spindle-targeted drugs in clinical use today bind tubulin and lead to mitotic arrest by perturbing the dynamic state of the assembly and disassembly of microtubules from their constituent tubulin building blocks. These drugs include the microtubule-stabilizing taxanes, which inhibit depolymerization, and the microtubule-destabilizing vinca alkaloids, which promote depolymerization. Microtubules are involved in many cellular functions in addition to mitosis, and consequently, tubulin-binding drugs are associated with a number of adverse effects, including peripheral neuropathy. Cytokinetics has focused its attention on compounds that inhibit mitotic spindle function without binding tubulin. More specifically, the company sought to identify small molecules that inhibit kinesin spindle protein (KSP), a kinesin motor protein involved in mitotic spindle assembly. Members of the kinesin superfamily of motor proteins utilize a conserved, ATP-dependent motor domain to pull their cargo along microtubule tracks in a variety of cellular activities, especially cell division and other processes involving relatively long distances and/or large cells.2,3 KSP is required early in mitosis to establish mitotic spindle bipolarity, and for subsequent cell cycle progression. After performing a series of high- throughput primary screens and secondary cell phenotyping screens, the company focused its efforts on SB-715992, a KSP inhibitor that blocks assembly of functional mitotic spindles, resulting in arrest of the cell cycle in mitosis and subsequent cell death. During the summer of 2001 through early 2002, Cytokinetics and GlaxoSmithKline put SB-715992 through its paces in a series of preclinical tests. They concluded that this inhibitor might prove clinically effective as an antitumor agent; it did not cause neuropathy in animal models, prompting optimism that it may be well-tolerated by patients undergoing chemotherapy. Phase I clinical trials, currently underway, are designed to evaluate SB-715992 with regard to its safety and tolerability, and to characterize its pharmacokinetic and pharmacodynamic profiles. At the same time, Cytokinetics is evaluating a number of other leads, including additional chemotherapeutic candidates, as well as several sarcomere-directed molecules, which may prove to be effective treatments for heart failure and hypertension. --Deborah A. Fitzgerald References 1. K.W. Wood et al., "Past and future of the mitotic spindle as an oncology target," Curr Opin Pharmacol, 1:370-7, 2001. 2. L. S. Goldstein, A. V. Philp, "The road less traveled: Emerging principles of kinesin motor utilization," Annu Rev Cell Dev Biol, 15:141-83, 1999. 3. R.D. Vale, R.A. Milligan, "The way things move: Looking under the hood of molecular motor proteins," Science, 288:88-95, 2000. function sendData() { document.frm.pathName.value = location.pathname; result = false if (document.frm.score[0].checked) result = true; if (document.frm.score[1].checked) result = true; if (document.frm.score[2].checked) result = true; if (document.frm.score[3].checked) result = true; if (document.frm.score[4].checked) result = true; if (!result) alert("Please select") return result; } .myradio{background-color : #94bee5} Please indicate on a 1 - 5 scale how strongly you would recommend this article to your colleagues? Not recommended 1 2 3 4 5 Highly recommended Please register your vote

Cytoskeletal Pharmacopeia

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