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A potent tyrosine kinase inhibitor, lavendustin A [1], has been isolated from a butyl acetate extract of Streptomyces griseolavendus culture filtrate. It inhibits epidermal growth factor receptor-associated tyrosine kinase with an IC50 of 4.4 ng/ml, which is about 50 times more inhibitory than erbstatin. It does not inhibit protein kinase A or C. Its structure, determined by spectral data and total synthesis, is novel, having a tertiary amine in the center with substituted benzyl and phenyl groups. Lavendustin A competes with ATP and is noncompetitive with the peptide. Its structure-activity relationship is discussed.

ErbB2-negative breast tumors represent a significant therapeutic hurdle because of a lack of effective molecular targets. Although NOTCH proteins are known to be involved in mammary tumorigenesis, the functional significance of these proteins in ErbB2-negative breast tumors is not clear. In the present study, we examined the expression of activated NOTCH receptors in human breast cancer cell lines, including ErbB2-negative and ErbB2-positive cell lines. Activated NOTCH1 and NOTCH3 proteins generated by ;-secretase were detected in most of the cell lines tested, and both proteins activated CSL-mediated transcription. Down-regulation of NOTCH1 by RNA interference had little or no suppressive effect on the proliferation of either ErbB2-positive or ErbB2-negative cell lines. In contrast, down-regulation of NOTCH3 significantly suppressed proliferation and promoted apoptosis of the ErbB2-negative tumor cell lines. Down-regulation of NOTCH3 did not have a significant effect on the ErbB2-positive tumor cell lines. Down-regulation of CSL also suppressed the proliferation of ErbB2-negative breast tumor cell lines, indicating that the NOTCH-CSL signaling axis is involved in cell proliferation. Finally, NOTCH3 gene amplification was detected in a breast tumor cell line and one breast cancer tissue specimen even though the frequency of NOTCH3 gene amplification was low (<1%). Taken together, these findings indicate that NOTCH3-mediated signaling rather than NOTCH1-mediated signaling plays an important role in the proliferation of ErbB2-negative breast tumor cells and that targeted suppression of this signaling pathway may be a promising strategy for the treatment of ErbB2-negative breast cancers.

The 6-deoxyerythronolide B hydroxylase (EryF) is a soluble cytochrome P450 responsible for the stereospecific C-6 hydroxylation of the erythromycin precursor, 6-deoxyerythronolide B. Using the expression of the eryF gene in Escherichia coli [Andersen, J. F., & Hutchinson, C. R. (1992) J. Bacteriol. 174, 725-735] as the enzyme source, we examined the catalytic activity of the EryF protein toward several macrolide substrates related to 6-deoxyerythronolide B. The results of these studies were compared with measurements of the apparent dissociation constants for various substrates and with information from molecular modeling studies of the substrates and the enzyme-substrate complex. Only minor changes in the structure of 6-deoxyerythronolide B resulted in substrates with catalytic rates less than 1% of those seen with the natural substrate. Although the 9S epimer of 9-deoxo-9-hydroxy-6-deoxyerythronolide B was hydroxylated at a rate approximately equal to the natural substrate, the 9R epimer was hydroxylated at a 2-fold lower rate. Examination of molecular models revealed that the position of the 9-hydroxyl oxygen in the 9S epimer resembles that of the 9-oxo oxygen in the natural substrate more closely than in the 9R epimer. 8,8a-Deoxyoleandolide, which is identical to 6-deoxyerythronolide B except for the presence of a C-13 methyl group, and its (9S)-9-deoxo-9-hydroxy derivative were C-6 hydroxylated at a 4-fold lower rate than the natural substrate, and the 9-oxo form showed a substantially larger apparent dissociation constant.(ABSTRACT TRUNCATED AT 250 WORDS)

Sir:Nagstatin (1)

No abstract

The baumycins were found in culture filtrates of a daunomycin-producing strain1). In preliminary tests of the activity on L-1210, baumycin Al exhibited stronger activity than adriamycin or daunomycin. This was not repeated in other laboratories where a second sample was tested. Moreover, the yield of baumycin Al was very small. Consequently, the simplest 4'-O

No abstract