Reference Detail

Ref Type Journal Article
PMID (26469692)
Authors Yu Y, Savage RE, Eathiraj S, Meade J, Wick MJ, Hall T, Abbadessa G, Schwartz B
Title Targeting AKT1-E17K and the PI3K/AKT Pathway with an Allosteric AKT Inhibitor, ARQ 092.
Journal PloS one
Vol 10
Issue 10
Date 2015
URL
Abstract Text 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.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
ARQ 751 ARQ 751 is an inhibitor of AKT1, AKT2, and AKT3, which may result in inhibition of the AKT/PI3K/MTOR pathway, thereby leading to tumor growth inhibition (PMID: 26469692).
ARQ092 Miransertib (ARQ092) is a pan-AKT inhibitor, resulting in inhibition of the PI3K/AKT signaling pathway and cell proliferation (PMID: 26469692).
Drug Name Trade Name Synonyms Drug Classes Drug Description
ARQ 751 Akt Inhibitor (Pan) 17 ARQ 751 is an inhibitor of AKT1, AKT2, and AKT3, which may result in inhibition of the AKT/PI3K/MTOR pathway, thereby leading to tumor growth inhibition (PMID: 26469692).
ARQ092 Miransertib ARQ-092 Akt Inhibitor (Pan) 17 Miransertib (ARQ092) is a pan-AKT inhibitor, resulting in inhibition of the PI3K/AKT signaling pathway and cell proliferation (PMID: 26469692).
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
AKT1 E17K endometrial cancer sensitive ARQ 751 Preclinical - Cell line xenograft Actionable In a preclinical study, an endometrial cell line xenograft model harboring AKT E17K was sensitive to ARQ 751, demonstrating inhibition of tumor growth (PMID: 26469692). 26469692
AKT1 E17K endometrial cancer sensitive ARQ092 Preclinical - Cell line xenograft Actionable In a preclinical study, an endometrial cell line xenograft model harboring AKT E17K was sensitive to ARQ092, demonstrating inhibition of tumor growth (PMID: 26469692). 26469692
Unknown unknown Advanced Solid Tumor not applicable ARQ 751 Preclinical - Cell culture Actionable In a preclinical study, treatment with ARQ 751 resulted in anti-proliferative activity in a variety of cancer cell lines in culture (PMID: 26469692). 26469692