Anticancer Agents Based on a New Class of Transition- State Analog Inhibitors for Serine and Cysteine Proteases

Abstract

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewingjnstructions.searching existing data sources, aatnerinoi and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect ofthis collection of information, including suggestions for reducing this burden. 1o Washington Headquarters Services, Directorate Tor Information Operations and Reports, 1215 Jefferson Davis Highway Suite1204, Arlington, VA 22202-4302, and to the Of/ice of Management and Budget, Paperwork Reduction Project (0704-0188), Washington, DC 20503. AGENCY USE ONLY (Leave blank)2. REPORT DATE August 1999 REPORT TYPE AND DATES COVERED PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Brown University Providence, RI 02912 SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES)Commander ABSTRACT (Maximum 200In this report we describe our efforts to develop a new class of competitive inhibitors for serine and cysteine proteases. These compounds are potential anticancer agents that would act by inhibiting metastasis and angiogenesis. Our work has shown that the 4-heterocyclohexanone pharmacophore can be used to synthesize effective inhibitors of both serine and cysteine proteases. We have rationally designed an inhibitor of the serine protease plasmin, and shown that it has good activity and specificity for plasmin over other proteases. In addition, we have used the 4-heterocyclohexanone pharmacophore to construct a combinatorial library of 400 different protease ^ inhibitors. These compounds are unique in that they are designed to interact with both the S and S binding sites of proteases; a feature which will increase both their potency and specificity. The library was screened against a variety of cancer-related proteases, which lead us to identify a second, even more potent inhibitor of plasmin. Where copyrighted material is quoted, permission has been obtained to use such material. SUBJECT TERMS Breast CancerWhere material from documents designated for limited distribution is quoted, permission has been obtained to use the material.Citations of commercial organizations and trade names in this report do not constitute an official Department of Army endorsement or approval of the products or services of these organizations.In conducting research using animals, the investigator(s) adhered to the "Guide for the Care and Use of Laboratory Animals," prepared by the Committee on Care and use of Laboratory Animals of the Institute of Laboratory Resources, national Research Council (NIH Publication No. 86-23, Revised 1985).For the protection of human subjects, the investigator(s) adhered to policies of applicable Federal Law 45 CFR 46.In conducting research utilizing recombinant DNA technology, the investigator(s) adhered to current guidelines promulgated by the National Institutes of Health.In the conduct of research utilizing recombinant DNA, the investigator(s) adhered to the NIH Guide...