High-Throughput Assay for G2 Checkpoint Inhibitors and Identification of the Structurally Novel Compound Isogranulatimide

Roberge, Michel; Berlinck, Roberto G. S.; Xu, Lin; Anderson, Hilary J.; Lim, Lynette Y.; Curman, Darko; Stringer, Cheri M.; Friend, Stephen H.; Davies, Peter; Vincent, Inez; Haggarty, Stephen J.; Kelly, Michael T.; Britton, Robert; Piers, Edward; Andersen, Raymond J.

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Articles| December 01 1998

High-Throughput Assay for G₂ Checkpoint Inhibitors and Identification of the Structurally Novel Compound Isogranulatimide^¹

Michel Roberge;

Michel Roberge

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Roberto G. S. Berlinck;

Roberto G. S. Berlinck

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Lin Xu;

Lin Xu

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Hilary J. Anderson;

Hilary J. Anderson

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Lynette Y. Lim;

Lynette Y. Lim

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Darko Curman;

Darko Curman

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Cheri M. Stringer;

Cheri M. Stringer

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Stephen H. Friend;

Stephen H. Friend

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Peter Davies;

Peter Davies

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Inez Vincent;

Inez Vincent

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Stephen J. Haggarty;

Stephen J. Haggarty

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Michael T. Kelly;

Michael T. Kelly

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Robert Britton;

Robert Britton

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Edward Piers;

Edward Piers

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Raymond J. Andersen

Department of Biochemistry and Molecular Biology, University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z3 [M. R., H. J. A., L. Y. L., D. C., S. J. H.];

Departments of Chemistry [R. G. S. B., L. X., R. B., E. P., R. J. A.] and Oceanography-Earth and Ocean Sciences [R. G. S. B., L. X., R. J. A.], University of British Columbia

,

Vancouver, British Columbia

,

Canada

V6T 1Z1;

Fred Hutchinson Cancer Research Center

,

Seattle, Washington 98105 [C. M. S., S. H. F.]

;

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University

,

Bronx, New York 1046 [P. D., I. V.]

; and

SeaTek Marine Biotechnology Inc.

,

Surrey, British Columbia

,

Canada

V4A 7M4 [M. T. K.]

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Author & Article Information

²

To whom requests for reprints should be addressed, at Department of Biochemistry and Molecular Biology, University of British Columbia, 2146 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Phone: (604) 822-2304; Fax: (604) 822-5227; E-mail: [email protected].

³

Present address: Instituto de Quimica de Sao Carlos, Universidade de Sao Paulo, CP 780, CEP 13560-970, Sao Carlos, S.P., Brazil.

Received: July 01 1998

Accepted: October 09 1998

Online ISSN: 1538-7445

Print ISSN: 0008-5472

1998

American Association for Cancer Research, Inc.

Cancer Res (1998) 58 (24): 5701–5706.

Abstract

Treatment of cancer cells lacking p53 function with G₂ checkpoint inhibitors sensitizes them to the toxic effects of DNA damage and has been proposed as a strategy for cancer therapy. However, few inhibitors are known, and they have been found serendipitously. We report the development of a G₂ checkpoint inhibition assay that is suitable for high-throughput screening and its application to a screen of 1300 natural extracts. We present the isolation of a new G₂ checkpoint inhibitor, the structurally novel compound isogranulatimide. In combination with γ-irradiation, isogranulatimide selectively kills MCF-7 cells lacking p53 function.

¹

Supported by the Canadian Breast Cancer Research Initiative (to M. R.), National Cancer Institute of Canada (to R. J. A.), Natural Sciences and Engineering Research Council of Canada (R. J. A.), and Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil (to R. G. S. B.).

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1998

American Association for Cancer Research, Inc.

High-Throughput Assay for G₂ Checkpoint Inhibitors and Identification of the Structurally Novel Compound Isogranulatimide^¹

Abstract

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High-Throughput Assay for G2 Checkpoint Inhibitors and Identification of the Structurally Novel Compound Isogranulatimide1

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High-Throughput Assay for G₂ Checkpoint Inhibitors and Identification of the Structurally Novel Compound Isogranulatimide^¹