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

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.]

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 -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.).

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: michel@otter.biochem.ubc.ca.

³ Present address: Instituto de Quimica de Sao Carlos, Universidade de Sao Paulo, CP 780, CEP 13560-970, Sao Carlos, S.P., Brazil.

Received 7/ 1/98. Accepted 10/ 9/98.

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