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|Ref Type||Journal Article|
|Authors||Smith MC, Mader MM, Cook JA, Iversen P, Ajamie R, Perkins E, Bloem L, Yip YY, Barda DA, Waid PP, Zeckner DJ, Young DA, Sanchez-Felix M, Donoho GP, Wacheck V|
|Title||Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth.|
|Abstract Text||The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival. LY3023414 is a complex fused imidazoquinolinone with high solubility across a wide pH range designed to inhibit class I PI3K isoforms and mTOR kinase. Here, we describe the in vitro and in vivo activity of LY3023414. LY3023414 was highly soluble at pH 2-7. In biochemical testing against approximately 266 kinases, LY3023414 potently and selectively inhibited class I PI3K isoforms, mTORC1/2, and DNA-PK at low nanomolar concentrations. In vitro, inhibition of PI3K/AKT/mTOR signaling by LY3023414 caused G1 cell-cycle arrest and resulted in broad antiproliferative activity in cancer cell panel screens. In vivo, LY3023414 demonstrated high bioavailability and dose-dependent dephosphorylation of PI3K/AKT/mTOR pathway downstream substrates such as AKT, S6K, S6RP, and 4E-BP1 for 4 to 6 hours, reflecting the drug's half-life of 2 hours. Of note, equivalent total daily doses of LY3023414 given either once daily or twice daily inhibited tumor growth to similar extents in multiple xenograft models, indicating that intermittent target inhibition is sufficient for antitumor activity. In combination with standard-of-care drugs, LY3023414 demonstrated additive antitumor activity. The novel, orally bioavailable PI3K/mTOR inhibitor LY3023414 is highly soluble and exhibits potent in vivo efficacy via intermittent target inhibition. It is currently being evaluated in phase I and II trials for the treatment of human malignancies. Mol Cancer Ther; 15(10); 2344-56. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|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 G118D||lung non-small cell carcinoma||sensitive||LY3023414||Preclinical - Cell line xenograft||Actionable||In a preclinical study, LY3023414 inhibited proliferation of non-small cell lung cancer cells harboring PIK3CA G118D in culture, resulted in tumor growth inhibition in cell line xenograft models (PMID: 27439478).||27439478|
|PTEN inact mut||kidney cancer||sensitive||LY3023414||Preclinical - Cell line xenograft||Actionable||In a preclinical study, LY3023414 inhibited proliferation of renal cancer cells harboring PTEN inactivating mutation in culture, resulted in tumor growth inhibition in cell line xenograft models (PMID: 27439478).||27439478|
|PIK3CA E545K||leukemia||sensitive||LY3023414||Preclinical||Actionable||In a preclinical study, LY3023414 inhibited tumor growth in a transgenic animal model of leukemia driven by PIK3CA E545K (PMID: 27439478).||27439478|
|PTEN loss||glioblastoma||sensitive||LY3023414||Preclinical - Cell line xenograft||Actionable||In a preclinical study, LY3023414 inhibited Pi3k/mTor signaling and proliferation in PTEN deficient glioblastoma cells in culture, and resulted in tumor growth inhibition in cell line xenograft models (PMID: 27439478).||27439478|