Reference Detail

Ref Type

Journal Article

PMID

(24634413)

Authors

Yu P, Laird AD, Du X, Wu J, Won KA, Yamaguchi K, Hsu PP, Qian F, Jaeger CT, Zhang W, Buhr CA, Shen P, Abulafia W, Chen J, Young J, Plonowski A, Yakes FM, Chu F, Lee M, Bentzien F, Lam ST, Dale S, Matthews DJ, Lamb P, Foster P

Title

Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathway.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	13	5	2014 May	1078-91	Mol Cancer Ther

URL

Abstract Text

Activation of the PI3K (phosphoinositide 3-kinase) pathway is a frequent occurrence in human tumors and is thought to promote growth, survival, and resistance to diverse therapies. Here, we report pharmacologic characterization of the pyridopyrimidinone derivative XL765 (SAR245409), a potent and highly selective pan inhibitor of class I PI3Ks (α, β, γ, and δ) with activity against mTOR. Broad kinase selectivity profiling of >130 protein kinases revealed that XL765 is highly selective for class I PI3Ks and mTOR over other kinases. In cellular assays, XL765 inhibits the formation of PIP(3) in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL765 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL765 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of approximately 24 hours. Repeat dose administration of XL765 results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is associated with antiproliferative, antiangiogenic, and proapoptotic effects.

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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
Voxtalisib	Voxtalisib	5	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Voxtalisib		XL765\|XL-765\|SAR245409\|SAR-245409	mTOR Inhibitor 51 PI3K Inhibitor (Pan) 42	Voxtalisib (XL765) inhibits both PI3K and mTOR kinases and results in inhibition of PI3K pathway signaling, thereby possibly leading to inhibition of cell proliferation, reduced tumor vascularization, and inhibition of tumor growth (PMID: 24634413, PMID: 31870556).

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
PTEN inact mut	glioblastoma	sensitive	SF1126	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a glioblastoma cell line harboring a PTEN inactivating mutation (PMID: 24634413) was sensitive to SF1126, demonstrating inhibition of tumor growth in cell line xenograft models (PMID: 18172313).	18172313 24634413
PTEN loss	breast adenocarcinoma	sensitive	Voxtalisib	Preclinical - Cell culture	Actionable	In a preclinical study, a breast adenocarcinoma cell line harboring PTEN loss was sensitive to XL765 (SAR245409), demonstrating inhibition of cell proliferation in culture (PMID: 24634413).	24634413
PTEN loss	prostate cancer	sensitive	Voxtalisib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a prostate cancer cell line with PTEN loss was sensitive to XL765 (SAR245409) treatment, demonstrating inhibition of the PI3K pathway and decreased colony formation in culture, and inhibition of tumor growth and reduced tumor vascularization in cell line xenograft models (PMID: 24634413).	24634413
PIK3CA E545K	breast cancer	sensitive	Voxtalisib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a breast cancer cell line harboring PIK3CA E545K was sensitive to XL765 (SAR245409), demonstrating inhibition of cell proliferation and colony formation in culture, and inhibition of tumor growth in cell line xenograft models (PMID: 24634413).	24634413
PTEN loss	prostate cancer	sensitive	SF1126	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a glioblastoma cell line harboring PTEN loss (PMID: 24634413) was sensitive to SF1126, demonstrating a 76% decrease in tumor growth in cell line xenograft models (PMID: 18172313).	18172313 24634413
PTEN inact mut	glioblastoma	sensitive	Voxtalisib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a glioblastoma cell line harboring a PTEN inactivating mutation was sensitive to XL765 (SAR245409), demonstrating inhibition of cell proliferation in culture, and inhibition of tumor growth in cell line xenograft models (PMID: 24634413).	24634413
PIK3CA amp	ovarian cancer	sensitive	Voxtalisib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, an ovarian cancer cell line harboring PIK3CA E545K was sensitive to XL765 (SAR245409), demonstrating inhibition of cell proliferation in culture, and inhibition of tumor growth in cell line xenograft models (PMID: 24634413).	24634413