The
emergence of artemisinin resistance, combined with certain
suboptimal properties of ozonide agents arterolane and artefenomel,
has necessitated the search for new drug candidates in the endoperoxide
class. Our group has focused on trioxolane analogues with substitution
patterns not previously explored. Here, we describe the enantioselective
synthesis of analogues bearing a trans-3″
carbamate side chain and find these to be superior, both in vitro
and in vivo, to the previously reported amides. We identified multiple
analogues that surpass the oral efficacy of arterolane in the Plasmodium berghei model while exhibiting drug-like
properties (logD, solubility, metabolic stability) similar or superior
to next-generation clinical candidates like E209 and OZ609. While
the preclinical assessment of new analogues is still underway, current
data suggest the potential of this chemotype as a likely source of
future drug candidates from the endoperoxide class.
KRAS mutations drive a quarter of cancer mortality, and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell. We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation. We converted an FDA-approved MEK inhibitor into a ferrous iron–activatable drug conjugate (FeADC) and achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor-bearing animals, with tumor-selective drug activation, producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation, and FeADCs hold promise for improving the treatment of KRAS-driven solid tumors.
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