M2698 is an orally bioavailable, BBB penetrable p70S6K/Akt dual inhibitor, and is highly potent in vitro (IC50 1 nM for p70S6K, Akt1 and Akt3 inhibition; IC50 17 nM for pGSK3β indirect inhibition) and in vivo (IC50 15 nM for pS6 indirect inhibition), and relatively selective (only 6/264 kinases had an IC50 within 10-fold of p70S6K). Orally administered M2698 crossed the blood-brain barrier in rats and mice, with brain tumor exposure 4-fold higher than non-disease brain. Dose-dependent inhibition of target substrate phosphorylation was observed in vitro and in vivo, indicating that M2698 blocked p70S6K to provide potent PAM pathway inhibition while simultaneously targeting Akt to overcome the compensatory feedback loop. M2698 demonstrated dose-dependent tumor growth inhibition in mouse xenograft models derived from PAM pathway-dysregulated human triple-negative (MDA-MB-468) and Her2-expressing breast cancer cell lines (MDA-MB-453 and JIMT-1), and reduced brain tumor burden and prolonged survival in mice with orthotopically implanted U251 glioblastoma.

KEYWORDS: M2698 | Supplier | p70S6K/Akt dual inhibitor | MSC2363318A | M-2698 | M 2698 | MSC-2363318A | MSC 2363318A | CT-M2698 | CAS [1379545-95-5] | Phosphatidylinositol | Akt | p70-RSK | Inhibitor | Enzymes