Product name
New Aza-Epothilones (azathilones) with Highly Potent Antiproliferative ActivitySummary
Highly potent hypermodified epothilone analogs, whose overall structural features deviate significantly from those of natural epothilone.Organization name
ETH ZurichProfile
Taxol and related analogs had long been the only class of compounds known to inhibit cancer cell proliferation through the stabilization of cellular microtubules. A number of structurally diverse natural products have been shown over the last decade to exert their antiproliferative activity through a "taxol-like" mechanism of action, thus providing a series of new lead structures for anticancer drug discovery.
Most prominent among these compounds are the bacterial natural products epothilones A and B, which exhibit potent in vitro and in vivo antitumor activity, including activity against taxol-resistant cell lines and tumor models, respectively. At least seven epothilone-derived agents have entered human clinical trials so far (including the natural product epothilone B), but the structures of all these compounds are still closely related to the natural epothilone scaffold. This may limit their potential for pharmacological differentiation from the natural product leads.
A significant part of research at ETH Zurich in the area of natural-products-based lead generation for anticancer drug discovery is focused on the development of new active scaffolds through the extensive structural modification (rather than simple peripheral derivatization) of epothilones. This has led to the discovery of highly potent hypermodified epothilone analogs, whose overall structural features deviate significantly from those of the natural epothilone manifold, but that are still based on a standard polyketide backbone.
In an alternative approach, they have investigated different types of aza-epothilones ("azathilones"), which are characterized by the replacement of a backbone carbon atom by nitrogen in the epothilone macrocycle. This has led to the identification of the compounds that are the subject of the current invention and that are exemplified by structures A1-A3 (see attachment).
Compound A1 induces tubulin polymerization with the same potency as epothilone A, arrests the cell cycle at G2/M (as epothilones), and inhibits the growth of drug-sensitive human cancer cells in vitro with comparable efficacy as epothilone A (IC50-values in the low single digit nM range). Compounds A2 and A3 are somewhat less active, but their IC50 values for human cancer cell growth inhibition are still in the 10-30 nM range.
Advantages
Aza-macrolides A1-A3 represent the first examples of a distinct new class of microtubule-stabilizing agents with unique structural features and, as indicated by some preliminary SAR data, a unique SAR profile. So far, only in vitro data are available for A1-A3, which have demonstrated a surprising level of antitumor activity. Given the structural differences between A1-A3 and natural epothilones it appears at least plausible that compounds A1-A3 or related analogs could distinguish themselves from the natural product leads by a different overall pharmacological profile. In contrast to epothilones A or B, A1-A3 do not anymore incorporate an epoxide moiety, which should lead to enhanced chemical and metabolic stability.
Contact
ETH Zurich
Corina Schütt
corina.schuett(at)sl.ethz.ch
About ETH Zurich
ETH Zurich is a science and technology university with an outstanding research record. ETH Zurich is the study, research and work place of 18,000 people from 80 nations. About 350 professors in 16 departments teach mainly in the engineering sciences and architecture, system-oriented sciences, mathematics and natural sciences areas and carry out research that is highly valued worldwide. As an internationally oriented institution of higher education and a nationally grounded one this forward-looking task is fulfilled in service to the Swiss nation. Twenty-one Nobel Laureates are connected with ETH Zurich. Maintaining and developing its top standing in the international competition among top universities is an important task of ETH Zurich.
Description File
ETH_Transfer_1.pdf
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