Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving hydrolase
Reexamination Certificate
1999-01-06
2001-03-27
Leary, Louise N. (Department: 1623)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving hydrolase
C435S007100, C435S006120, C514S172000, C514S182000, C514S518000, C585S350000
Reexamination Certificate
active
06207403
ABSTRACT:
BACKGROUND OF THE INVENTION
Plants and animals have yielded a number of chemical molecules having useful biological activity (e.g., anti-tumor activity). Particularly rich sources of biologically active chemicals are marine organisms, which comprise over half a million species. Marine organisms have been found to produce a variety of metabolic often having unprecedented chemical structures.
In recent years, an increasing number of natural products extracted from marine organisms have been reported to exhibit a variety of biological activities such as antimicrobial, antiviral, antifungal and anticancer activities. These include peptides, polyethers, alkaloids, prostanoids, and the like. Such compounds have been obtained from sponges, octocorals, algae, tunicates, nuclibranches, bryozoans and marine bacteria.
In particular, a number of anti-tumor and anti-fungal compounds have been extracted from marine life. For example, U.S. Pat. No. 4,729,996 discloses anti-tumor imidazole ring compounds isolated from the marine sponges
Teichaxinella morchella
and
Ptioocaulis walpersi.
U.S. Pat. No. 4,808,590 discloses nitrogen containing cyclic compounds isolated having antiviral, anti-tumor, and antifungal properties, isolated from the marine sponge Theoneloa sp. Similarly, U.S. Pat. No. 4,866,084 discloses bisindole alkaloids extracted from the marine sponge
Spongosorites ruetzleri
useful in treating certain classes of tumors, while U.S. Pat. No. 4,970,226 discloses bis-indole imidazole alkaloids and derivatives isolated from the marine sponge Spongosorites sp. which exhibit useful anti-tumor and antimicrobial properties.
Marine sponges, in particular, have proven to be a rich resource for biologically active compounds (see, e.g., Scheuer, P. J. (ed.) (1978-1983)
Marine Natural Products, Chemical and Biological Perspectives Vol. I-V,
Academic Press, New York; Faulkner (1977)
Tetrahedron,
33: 1421; Faulkner (1984)
Nat, Prod. Rep.
1: 551; Faulkner (1986)
Nat, Prod. Rep.
3: 1; Faulkner (1987)
Nat, Prod. Rep.
4: 539; Faulkner (1988)
Nat, Prod. Rep.
5: 613; Faulkner (1990)
Nat, Prod. Rep.
7: 269; Faulkner (1991)
Nat, Prod. Rep.
7: 269; Faulkner (1992)
Nat, Prod. Rep.
9: 323; Faulkner (1993)
Nat, Prod. Rep.
10: 497; Faulkner (1994)
Nat, Prod. Rep.
1 1: 355; Faulkner (1954)
Nat, Prod. Rep.
12: 223; Faulkner (1996)
Nat, Prod. Rep.
13: 75; Faulkner (1997)
Nat, Prod. Rep.
14: 256; and Faulkner (1985)
J. Am. Chem. Soc.
107: 4796-4798). However there exist literally thousands of species of marine sponges and these organisms are only beginning to be explored.
SUMMARY OF THE INVENTION
This invention provides novel compounds derived from a marine sponge, Haliclona (aka Adocia) sp., that specifically modulate (e.g., inhibit) kinesin activity by targeting the kinesin motor domain and mimicking the activity a microtubule. It is believed this mode of kinesin motor modulation is previously unknown. Thus, it was also a discovery of this invention that the kinesin-microtubule interaction site is a useful target for small molecule modulators of kinesin motor activity.
Because the compounds were initially derived from the marine sponge Haliclona (Adocia) sp. they are referred to herein as Adocia compounds or Adocia-derived compounds. Particularly preferred Adocia-derived compounds are adociasulfates. Thus, in one embodiment, this invention provides for the Adocia-derived compounds having the formulas shown herein, more preferably for the adociasulfate compounds having the formulas shown herein.
The Adocia-derived compounds are potent kinesin motor modulators that appear to block kinesin binding of microtubules. The compounds are potent anti-mitotic agents that are highly effective in vitro and in vivo. Thus, in another embodiment, this invention provides composition for the in vivo modulation (e.g., inhibition) of kinesin motor activity (e.g., in a cell). The compositions typically comprise any of the Adocia-derived kinesin motor inhibitors described herein in combination with a pharmacologically acceptable excipient.
In another embodiment, this invention provides methods of modulating (e.g., inhibiting) kinesin motor activity in a cell. The methods involve contacting the cell with one or more of the Adocia-derived kinesin modulators described herein. The cell, although preferably a mammalian cell, need not be so limited. Other suitable cells include, but are not limited to, fungal cells and microbial cells. The cell can be in vitro or in vivo. Where the method is practiced in a therapeutic context (e.g., to ameliorate the effects of a pathological condition characterized by hyperproliferation of one or more cells) the Adocia-derived kinesin modulators are preferably administered in a therapeutically effective dose.
In still another embodiment, this invention provides methods of assaying a test compound for kinesin modulatory activity. The methods involve contacting a microtubule and a kinesin motor (e.g. a kinesin motor protein) with one of the Adocia-derived kinesin modulators described herein and detecting a change in kinesin motor activity resulting from the contacting. In a particularly preferred embodiment, the method is practiced with one of the kinesin modulators of Formulas I, and III-VI, more preferably with one of the kinesin modulators of Formulas I or III. The change in motor activity is preferably detected through a motility assay, a binding assay, an ADP release assay, or an assay for anti-mitotic activity. Typically the change in activity is evaluated with reference to a negative control (e.g., typically the same assay, but lacking a kinesin motor modulator) and/or with reference to a positive control (e.g., typically the same assay, with a different kinesin motor inhibitor, preferably one whose activity has previously been characterized).
This invention also provides Adocia-derived kinesin modulator kits. The kits typically include a container containing one or more of the Adocia-derived kinesin modulator described herein. The kits can optionally include a pharmacological excipient and/or a delivery vehicle. When the excipient and/or delivery vehicle are provided they may be provided combined with the kinesin motor inhibitor or in a separate container for combination at the time of use. The kit can also include instructional materials describing the use of the compounds in any of the methods described herein.
In still another embodiment, this invention provides methods of modulating kinesin motor activity. The methods involve contacting the kinesin motor with a small organic molecule that competitively inhibits the kinesin motor at a microtubule binding site. In a particularly preferred embodiment, the small organic molecule is an Adocia-derived kinesin modulator as described herein or a a small organic molecule is identified according to the methods described herein.
This invention also provides methods of identifying an agent that modulates the kinesin inhibitory activity of an Adocia kinesin inhibitor (e.g., on of the Adocia sulfates or Adocia derived kinesin inhibitors described herein). The methods involve contacting a microtubule and/or a kinesin motor and/or an Adocia kinesin inhibitor with a candidate agent; and detecting a change in the kinesin inhibitory activity of the Adocia kinesin inhibitor resulting from the contacting , wherein a change indicates the identification of an agent that modulates the kinesin inhibitory activity of the Adocia kinesin inhibitor.
Methods are also provided for identifying an agent that interferes with the binding of an Adocia kinesin inhibitor with a kinesin. These methods involve contacting a kinesin and an Adocia kinesin inhibitor (e.g. an adocia sulfate or an adocia derived kinesin modulator described herein) with a candidate agent; and detecting a decrease in the binding of the Adocia kinesin inhibitor with the kinesin resulting from said contacting, wherein a decrease indicates the identification of an agent that interferes with the binding of the Adocia kinesin inhibitor and the kinesin.
Also provided herein is a
Berdelis Michael S.
Blackburn Christine L.
Faulkner David John
Goldstein Lawrence S. B.
Hopmann Cordula
Leary Louise N.
Medlen & Carroll LLP
The Regents of the University of California
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