As a critical component in the PI3K/AKT/mTOR pathway, AKT has become an attractive target for therapeutic intervention.
ARQ 092 and a next generation AKT inhibitor, ARQ 751 are selective, allosteric, pan-AKT and AKT1-E17K mutant inhibitors that potently inhibit phosphorylation of AKT. Biochemical and cellular analysis showed that
ARQ 092 and ARQ 751 inhibited AKT activation not only by dephosphorylating the membrane-associated active form, but also by preventing the inactive form from localizing into plasma membrane. In endometrial PDX models harboring mutant AKT1-E17K and other
tumor models with an activated AKT pathway, both compounds exhibited strong anti-
tumor activity. Combination studies conducted in in vivo
breast tumor models demonstrated that
ARQ 092 enhanced
tumor inhibition of a common chemotherapeutic agent (
paclitaxel). In a large panel of diverse
cancer cell lines,
ARQ 092 and ARQ 751 inhibited proliferation across multiple
tumor types but were most potent in
leukemia, breast, endometrial, and
colorectal cancer cell lines. Moreover, inhibition by
ARQ 092 and ARQ 751 was more prevalent in
cancer cell lines containing PIK3CA/PIK3R1 mutations compared to those with wt-PIK3CA/PIK3R1 or PTEN mutations. For both
ARQ 092 and ARQ 751, PIK3CA/PIK3R1 and AKT1-E17K mutations can potentially be used as predictive
biomarkers for patient selection in clinical studies.