V-ATPase inhibitor targets Ras-mutant cancers
IN BRIEF
02 September 2022
Direct inhibition of mutant KRAS remains challenging, and alternative strategies aimed at targeting concomitant metabolic adaptations, such as the high levels of autophagy, are emerging. Here, Tolani et al. report the discovery and characterization of 249C, which binds to and inhibits V-ATPase, resulting in inhibition of autophagy, macropinocytosis, and lysosomal acidification. 249C selectively kills KRAS/BRAF-mutant cells, exhibiting highest activity against KRAS-G13D and KRAS-G12V cells. In mouse xenograft models of mutant KRAS lung and colon cancer, 249C inhibited tumour growth with minimal toxicity. The molecule is currently undergoing phase I trials.
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doi: https://doi.org/10.1038/d41573-022-00151-w
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