Available Technology
Small molecule inhibitor of Cdc20 induces mitotic arrest
Technology:
Small molecule inhibitor
Markets Addressed
Antimitotic agents, including taxanes and the vinca alkaloids, represent one of the most important classes of anticancer therapies (2005 sales > $5 billion). Despite their activity across a broad range of cancers, these agents are limited by debilitating side effects such as peripheral neuropathy, a consequence of perturbing tubulin function in neurons. Furthermore, these side effects limit the dose of the agent that can be used, limiting their anticancer efficacy.
This invention has potential use in the following areas:
• Cancer: Agents that prevent the association of Cdc20 with APC which inhibit APC activation is a novel approach for the treatment of cancer and other disorders associated with cell division.
In addition, this agent may be potentially be used for:
• CNS disease: APC is also known to regulate functions in the CNS and control rates of axon growth. Agents that inhibit APC activation may have therapeutic benefit for CNS disorders.
• Regenerative medicine: Low doses of the prodrug induce mitotic delay rather than mitotic arrest, suggesting that APC inhibitors may enhance the fidelity of chromosome segregation in cases where spindle checkpoint function is compromised. By preventing chromosome missegregation, APC inhibitors may enhance the long term viability of cells in culture (such as stem cell lines), and the fidelity of chromosome segregation in early embryos following in vitro fertilization, increasing the fraction of viable embryos. There is currently no other pharmacological tool that can be used for this purpose, as all other antimitotic compounds interfere with chromosome segregation by disrupting the function of the mitotic spindle.
Innovations and Advantages
Antitubulin agents arrest cancer cells in mitosis by interfering with the function of the mitotic spindle, the cellular apparatus that segregates chromosomes in mitosis. By perturbing spindle function, antitubulin agents activate a checkpoint pathway (the spindle assembly checkpoint) that arrests cells in mitosis, ultimately leading to cell death. Another checkpoint is a ubiquitin ligase called the Anaphase-Promoting Complex (APC), a multisubunit ubiquitin ligase that regulates the timing of mitotic exit and the G1/S transition. In prometaphase, the APC is activated by Cdc20, leading to ubiquitination and degradation of several kinases.
This invention provides new insights into APC regulation and demonstrates that the APC is a druggable target amenable to pharmacologic intervention, and may provide an opportunity to develop novel antimitotic agents.
Using a phenotypic screen in Xenopus cell cycle extracts, researchers in the King laboratory identified a small molecule that specifically inhibits the activation of the APC, but not other ubiquitin ligases. Specifically, this molecule interferes with the binding of Cdc20 to the APC. The laboratory further synthesized a cell-permeable prodrug of the agent which induces strong mitotic arrest and subsequent apoptosis in a wide variety of human cancer cell lines.
Advantages over current antimitotic agents:
• Higher efficacy: Studies of the prodrug’s mechanism revealed new aspects of mitotic regulation that indicate that direct inhibition of APC represents a much more effective mechanism for inducing mitotic arrest than agents that activate the spindle checkpoint (including all antitubulin agents as well as newer antimitotics such as inhibitors of mitotic kinesins). In addition, the lab demonstrated that whereas conventional antimitotic agents require continued protein synthesis to maintain mitotic arrest, arrest induced by an APC inhibitor does not. These significant mechanistic distinctions may enable APC inhibitors to produce a more profound mitotic arrest than can be achieved by conventional antimitotics.
• Improved side effect profile: Small molecules that directly inhibit the APC may produce an equivalent antimitotic effect, without causing the side effects that result from inhibiting tubulin function in nondividing cells. This selectivity may enable normal dividing cells, such as those in the gut and bone marrow, to more easily tolerate treatment, and resume normal division following removal of the drug. This may enable much higher concentrations of APC inhibitors to be used in cancer therapy than antitubulin agents.
• Potential use as radiation therapy adjunct: Mitotic cells are much more sensitive to ionizing radiation than interphase cells, because DNA repair pathways are inactivated during mitosis. Therefore, it may be possible to temporarily arrest cells in mitosis with an APC inhibitor, treat with radiation, and then remove the drug. This approach is not feasible with conventional antimitotics because they induce a high rate of errors in chromosome segregation when removed.
Additional Information
Intellectual Property Status: Patent(s) pending
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Inventor(s):
King, Randall W.
Zeng, Xing
Categories:
For further information, please contact:
Grant Zimmermann, Director of Business Development
(617) 495-3067
Reference Harvard Case #3283