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

[0020]In certain embodiments, down regulation of VDAC activity or protein levels, a non-limiting example of VDAC down regulation is RNA interference-mediated knockdown of VDAC2 or VDAC3, caused resistance to erastin. In certain embodiments, VDAC2 and 3 isoforms of VDAC are implicated in erastin's mechanism of action. In other embodiments, wherein purified mitochondria expressing VDAC3 were used, erastin increased the permeability of the outer mitochondrial membrane, demonstrating that erastin acts through a gain-of-function mechanism, by opening VDAC2 and VDAC3 channels.

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 have been difficult to target effectively with small molecules4.

Small molecules that activate the GTPase activity of RAS proteins might also be developed, although such an approach may be challenging to realize4.

Images