Reference Detail

Ref Type

Journal Article

PMID

(27186432)

Authors

Machl A, Wilker EW, Tian H, Liu X, Schroeder P, Clark A, Huck BR

Title

M2698 is a potent dual-inhibitor of p70S6K and Akt that affects tumor growth in mouse models of cancer and crosses the blood-brain barrier.

Journal	Vol	Issue	Date	Pages	Journal Short Title
American journal of cancer research	6	4	2016	806-18	Am J Cancer Res

URL

Abstract Text

Dysregulated PI3K/Akt/mTOR (PAM) pathway signaling occurs in ~30% of human cancers, making it a rational target for new therapies; however, the effectiveness of some PAM pathway inhibitors, such as mTORC rapalogs, may be compromised by a compensatory feedback loop leading to Akt activation. In this study, the p70S6K/Akt dual inhibitor, M2698 (previously MSC2363318A), was characterized as a potential anti-cancer agent through examination of its pharmacokinetic, pharmacodynamic and metabolic properties, and anti-tumor activity. M2698 was 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. These findings highlight M2698 as a promising PAM pathway inhibitor whose unique mechanism of action and capacity to pass the blood-brain barrier warrant clinical investigation in cancers with PAM pathway dysregulation, and those with central nervous system involvement.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
M2698	M2698	3	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
M2698		MSC2363318A\|M-2698	Akt Inhibitor (Pan) 21 S6 Kinase Inhibitor 5	M2698 (MSC2363318A) binds to and inhibits the activity of P70S6K and AKT, which prevents the activation of the PI3K-AKT-P70S6K signaling pathway, thereby inhibiting tumor cell proliferation (PMID: 27186432, PMID: 28376174).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA H1047R	breast cancer	sensitive	M2698	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a breast cancer xenograft model harboring PIK3CA H1047R was sensitive to M2698 (MSC2363318A), demonstrating inhibition of tumor growth (PMID: 27186432).	27186432
PTEN loss	triple-receptor negative breast cancer	sensitive	M2698	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a triple-receptor negative breast cancer xenograft model harboring PTEN loss was sensitive to M2698 (MSC2363318A), demonstrating inhibition of tumor growth and tumor regression (PMID: 27186432).	27186432