High throughput screening of a large and diverse collection of commercially available synthetic organic compounds (excluding peptides and oligonucleotides) has furnished us with several potent and selective classes of inhibitors of the immortalizing enzyme telomerase. In anticipation of a major expansion of our efforts to discover new chemical entities with anti-tumor properties, additional funding Is being sought. The award of this grant will be applied towards personnel support and new instrumentation. These resources will accelerate the drug discovery process In several important ways. First, we envision the selection and construction of random and focused chemical combinatorial libraries. In addition, more traditional medicinal chemistry techniques will supplement the generation of chemical diversity that arises from the rapid synthesis of analogs. This combined approach will optimize the process of lead generation. The results of this research program are expected to expand our understanding of structure activity relationships required for telomerase inhibition. Candidates with the highest potency and selectivity will be evaluated for in vivo efficacy through the integrated efforts of collaborators at Geron and the Memorial Sloan Kettering Cancer Center. During the final phases of this grant, our most critical objective will be to refine the structural requirements of lead compounds with respect to desirable drug properties, such as oral bioavailability and biological duration of action. Since relatively large quantities of a drug are required for thorough preclinical pharmacological evaluation, process chemistry will be developed to accommodate this demand.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program--Cooperative Agreements (U19)
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Gammaitoni, Loretta; Weisel, Katja C; Gunetti, Monica et al. (2004) Elevated telomerase activity and minimal telomere loss in cord blood long-term cultures with extensive stem cell replication. Blood 103:4440-8
Wang, Eunice S; Wu, Kaida; Chin, Allison C et al. (2004) Telomerase inhibition with an oligonucleotide telomerase template antagonist: in vitro and in vivo studies in multiple myeloma and lymphoma. Blood 103:258-66
Asai, Akira; Oshima, Yuko; Yamamoto, Yoshihiro et al. (2003) A novel telomerase template antagonist (GRN163) as a potential anticancer agent. Cancer Res 63:3931-9
Franco, S; Ozkaynak, M F; Sandoval, C et al. (2003) Telomere dynamics in childhood leukemia and solid tumors: a follow-up study. Leukemia 17:401-10
Wu, Kai-Da; Orme, Lisa M; Shaughnessy Jr, John et al. (2003) Telomerase and telomere length in multiple myeloma: correlations with disease heterogeneity, cytogenetic status, and overall survival. Blood 101:4982-9
Boklan, Jessica; Nanjangud, Gouri; MacKenzie, Karen L et al. (2002) Limited proliferation and telomere dysfunction following telomerase inhibition in immortal murine fibroblasts. Cancer Res 62:2104-14
Franco, S; MacKenzie, K L; Dias, S et al. (2001) Clonal variation in phenotype and life span of human embryonic fibroblasts (MRC-5) transduced with the catalytic component of telomerase (hTERT). Exp Cell Res 268:14-25
Engelhardt, M; Mackenzie, K; Drullinsky, P et al. (2000) Telomerase activity and telomere length in acute and chronic leukemia, pre- and post-ex vivo culture. Cancer Res 60:610-7
Albanell, J; Bosl, G J; Reuter, V E et al. (1999) Telomerase activity in germ cell cancers and mature teratomas. J Natl Cancer Inst 91:1321-6
Engelhardt, M; Ozkaynak, M F; Drullinsky, P et al. (1998) Telomerase activity and telomere length in pediatric patients with malignancies undergoing chemotherapy. Leukemia 12:13-24

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