Compunds and compositions that cause non-apoptotic cell death and uses thereof

Abstract

The present invention relates to erastin analogs, particularly compounds of formulae I and II, including compounds 1-20, 22-24, 34, and 40. The invention also relates to pharmaceutical compositions containing such analogs and to methods of treating conditions in a mammal with such analogs and pharmaceutical compositions.

Description

CLAIM TO BENEFIT[0001]This application is a continuation-in-part of international application no. PCT / US2007 / 014360 filed Jun. 19, 2007, which international application is incorporated by reference as if recited in full herein. The international application claims the benefit of U.S. Provisional Application No. 60 / 814,864, filed Jun. 19, 2006, U.S. Provisional Application No. 60 / 817,665, filed Jun. 29, 2006, and U.S. Provisional Application No. 60 / 861,560, filed Nov. 29, 2006, each of which is incorporated by reference as if recited in full herein.GOVERNMENT FUNDING[0002]The work described herein was funded, in whole or in part, by National Cancer Institute Grant R01CA097061. The United States government may have certain rights in the invention.FIELD OF THE INVENTION[0003]The invention is directed to, inter alia, genotype-selective anti-tumor drugs that induce cell death by a non-apoptotic mechanism. The invention is further directed to uses of compounds and compositions to treat pa...

AI Technical Summary

Benefits of technology

[0037]To test this gain-of-function hypothesis, VDAC protein levels were reduced using a lentiviral shRNA expression system (Moffat et al. 2006). Five shRNA constructs were created targeting each VDAC isoform and their effects on erastin resistance were tested. In certain embodiments, knockdown of VDAC3 caused significant resistance to erastin. In another embodiment, there is a degree of erastin resistance when VDAC2 was knocked down. The isoform specificity of each shRNA reagent was confirmed at the mRNA and protein level. These results are consistent with a gain of function mechanism, such as increasing permeability of the outer mitochondrial membrane. In contrast, overexpression of VDAC3 alone in BJ-TERT cells yielded no increase in sensitivity to erastin, suggesting that other downstream aspects of RAS-RAF-MEK signaling are needed to sensitize cells to erastin, such as increasing rates of glycolysis and respiration. Overall, these results are consistent with a gain of function mechanism involving erastin and VDAC2/3. This effect is specific to erastin, but not other lethal compounds, e.g., VDAC2-deficient embryonic stem cells have been shown to be more sensitive, not less sensitive, to staurosporine and etoposide. (Cheng, E. H., Sheiko, T. V., Fisher, J. K., Craigen, W. J. & Korsmeyer, S. J. VDAC2 inhibits BAK activation and mitoch

Problems solved by technology

A limitation of this approach is that some oncogenic proteins are not amenable to inhibition with a small molecule.

For example, the RAS oncoproteins are implicated in the genesis of numerous human tumors, but h

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