A new Tolypocladium sp. was obtained through a crowdsourcing initiative. Triggering the expression of a silent biosynthetic pathway in this fungus was achieved through chemical epigenetics, culture medium manipulation, and co–culture to yield the unique polyketide–shikimate–NRPS–hybrid compound, maximiscin, which demonstrated in vivo antitumor activity.
Triple negative breast cancers (TNBC) are aggressive malignancies with no effective targeted therapies. Recent gene expression profiling of these heterogeneous cancers and the classification of cell line models now allows for the identification of compounds with selective activities against molecular subtypes of TNBC. The natural product deguelin was found to have selective activity against MDA-MB-453 and SUM-185PE cell lines, which both model the luminal androgen receptor (LAR) subtype of TNBC. Deguelin potently inhibited proliferation of these cells with GI50 values of 30 nM and 61 nM, in MDA-MB-453 and SUM-185PE cells, respectively. Deguelin had exceptionally high selectivity, 197 to 566-fold, for these cell lines compared to cell lines representing other TNBC subtypes. Deguelin’s mechanisms of action were investigated to determine how it produced these potent and selective effects. Our results show that deguelin has dual activities, inhibiting PI3K/Akt/mTOR signaling, and decreasing androgen receptor (AR) levels and nuclear localization. Based on these data, we hypothesized that the combination of the mTOR inhibitor rapamycin and the antiandrogen enzalutamide would have efficacy in LAR models. Rapamycin and enzalutamide showed additive effects in MDA-MB-453 cells, and both drugs had potent antitumor efficacy in a LAR xenograft model. These results suggest that the combination of antiandrogens and mTOR inhibitors might be an effective strategy for the treatment of androgen receptor-expressing TNBC.
Two new dimeric epipolythiodiketopiperazines,
preussiadins A (1) and B (2), together with
two known diastereomers, leptosins C (6) and A (7), were obtained from the mycelia of a Preussia typharum isolate. The structures of the new compounds were established by
spectroscopic methods, and the absolute configurations of 1 and 2 were assigned by chemical transformations and
comparisons of quantum chemical ECD and VCD calculations to experimental
data. Compound 1 exhibited potent cytotoxic activity
in the NCI-60 cell line panel with an average LC50 value
of 251 nM. Further studies demonstrated that 1 circumvents
P-glycoprotein-mediated drug resistance, yet had no significant antitumor
activity in a xenograft UACC-62 melanoma model.
The taccalonolides are microtubule stabilizers that covalently bind tubulin and circumvent clinically relevant forms of resistance to other drugs of this class. Efforts are underway to identify a taccalonolide with optimal properties for clinical development. The structurally similar taccalonolides AF and AJ have comparable microtubule stabilizing activities in vitro, but taccalonolide AF has excellent in vivo antitumor efficacy when administered systemically while taccalonolide AJ does not elicit this activity even at its maximum tolerated dose. The hypothesis that pharmacokinetic differences underlie the differential efficacies of taccalonolides AF and AJ was tested. The effects of serum on their vitro potency, metabolism by human liver microsomes, and in vivo pharmacokinetic properties were evaluated. Taccalonolides AF and AJ were found to have elimination half-lives of 44 and 8.1 min, respectively. Furthermore, taccalonolide AJ was found to have excellent and highly persistent antitumor efficacy when administered directly to the tumor, suggesting that the lack of antitumor efficacy seen with systemic administration of AJ is likely due to its short half-life in vivo. These results help define why some, but not all, taccalonolides inhibit the growth of tumors at systemically tolerable doses and prompt studies to further improve their pharmacokinetic profile and antitumor efficacy.
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