Tumor xenografts, inhibition

Hemiasterlin (206) Oligopeptide E7974 (207) Oncology Tubulin assembly inhibition Phase I (against a variety of human tumor xenografts) Eisai 944... 

Plumb, J.A., Finn, P.W., Williams, R.J., Bandara, M.J., Romero, M.R., Watkins, C.J. et al. (2003) Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXDIOI. Molecular Cancer Therapeutics, 2, 721-728. 

ARRY-334543 shows robust efficacy in several hiunan tumor xenograft models, including BT-474, MDA-MB-453, H1650, Calu3, and A431 [81,82]. Target inhibition in vivo or PK/PD relationships have not been reported. ARRY-334543 recently entered phase I trials no data have been reported. 

HKI-272 has shown activity in animal models daily doses of 40 mg/kg result in greater than 75% tumor growth inhibition in xenograft models of both BT-474 breast carcinoma and A431 epidermal carcinoma [93]. Reports of the phase I evaluation of HKI-272 are not yet available. 

The most potent PDKl kinase inhibitor reported to date is UCN-01 (compound 16 Fig. 4 IC50 = 6 to 33 nM) [101], a staurosporine analogue isolated from the culture broth of Streptomyces sp. Originally developed as an inhibitor of calcium-dependent PKC, UCN-01 has the capacity to inhibit a broad spectrum of kinases [102], including other members of the AGC subfamily of kinases (e.g., IC5o = 491nM for PKB) [103]. UCN-Ol-induced PDKl inhibition has also been observed in in vivo murine and human tumor xenografts [101]. 

The group at Millennium Pharmaceuticals has claimed MLN-8054 (97) to be the first kinase inhibitor selective for Aurora-A over Aurora-B, which gives robust inhibition of human tumor xenografts [228-230]. Treatment of cultured human tumor cells with 97 resulted in the accumulation of mitotic cells with spindle abnormalities, a phenotype consistent with selective Aurora-A inhibition. In a pharmacodynamic model the time-dependent accumulation of... 

Nagasu T, Yoshimatsu K, Rowell C, et al. Inhibition of human tumor xenograft growth by treatment with the famesyl transferase inhibitor B956. Cancer Res 1995 55 5310-5314. 

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