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Optimization of dipeptide-linked benzimidazole topoisomerase 1 poisons

Award Information

Department of Health and Human Services
Award ID:
Program Year/Program:
2009 / STTR
Agency Tracking Number:
Solicitation Year:
Solicitation Topic Code:
Solicitation Number:
Small Business Information
1214 Research Blvd Suite 2014 HUMMELSTOWN, PA 17036-9196
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Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
Phase 1
Fiscal Year: 2009
Title: Optimization of dipeptide-linked benzimidazole topoisomerase 1 poisons
Agency: HHS
Contract: 1R41CA132413-01A2
Award Amount: $260,988.00


DESCRIPTION (provided by applicant): Derivatives of camptothecin (CPT) that inhibit Topoisomerase I (Top1) activity have demonstrated clinical utility in the treatment of various cancers. However, limitations in CPT pharmaceutical properties have driven th e search for new CPT-like poisons that target the Top1 protein-DNA cleavage complex. We hypothesized that bifunctional agents that simultaneously bind to the DNA minor groove and the nose-cone region of the Top1 protein would be effective poisons with phar maceutical properties that are superior to the CPT congeners. Such compounds also should be effective against tumors that are otherwise resistant to the CPT structural class of poisons and should generally exhibit reduced toxicity compared to the CPT- clas s of agents such as topotecan. Structural insights from Top1-DNA crystal structures were used to design a small library of N-acetyl dipeptides linked to Hoechst 33258, a DNA minor groove binder. Screening of the library against a in vitro assays and subseq uent library deconvolution afforded a high affinity (EC50 ~ 50 nM) agent, LL217, that also caused growth arrest of several tumor cell lines. Subsequent replacement of the Hoechst with a phenyl- substituted monobenzimidazole provided the agent MB1 that exhi bits tumor cell line killing activity similar to LL217 but with substantially reduced off-target effects. Biochemical assays performed with LL217 and MB1 demonstrate that the primary modality of action in tumor cell lines is cell cycle arrest due to inhibi tion of Top1 activity. Our long-term goal is to translate MB1 into a clinically efficacious drug. Our immediate goal is to produce a refined lead compound with sufficient tissue culture and murine xenograft data to support further development. The immediat e goals will be achieved via four specific aims: (1) the structure of MB1 will be slightly modified to facilitate solution phase syntheses, (2) the in vitro and cellular activities of the MB1 derivatives will be assayed and compared to topotecan, (3) the p otential therapeutic efficacy of MB1 will be evaluated in murine xenograft tumor models as compared to topotecan, and (4) the pharmaceutical properties of MB1 and topotecan will be evaluated. PUBLIC HEALTH RELEVANCE: Cancer has recently surpassed cardiova scular disease as a major cause of morbidity and mortality in the United States. Although new classes of chemotherapeutic agents are needed, it is also desirable to develop agents with improved pharmaceutical properties that target clinically validated tar gets. The camptothecin class of agents used in the clinic specifically target the Topoisomerase 1 enzyme. However, their poor solubilities and stabilities require the use of large doses, which increases the chances for adverse effects to the patient. The a gents described here also target Topoisomerase 1, but they are expected to be more bioavailable and, thus, offer an improvement to the camptothecin class of agents. Because these agents are also structurally distinct, it is expected that they will be clini cally efficacious against cancers that have developed resistance to the camptothecins.

Principal Investigator:

Craig C. Beeson

Business Contact:

Charles D. Smith
Small Business Information at Submission:

1214 Research Blvd Suite 1016 Hummelstown, PA 17036

EIN/Tax ID: 251901043
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
Research Institution Information:
Office of Research and Sponsored Programs
19 Hagood Ave., Suite 606
CHARLESTON, SC 29425 6271
RI Type: Nonprofit college or university