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|Ref Type||Journal Article|
|Authors||Hart S, Novotny-Diermayr V, Goh KC, Williams M, Tan YC, Ong LC, Cheong A, Ng BK, Amalini C, Madan B, Nagaraj H, Jayaraman R, Pasha KM, Ethirajulu K, Chng WJ, Mustafa N, Goh BC, Benes C, McDermott U, Garnett M, Dymock B, Wood JM|
|Title||VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Dysregulation of the PI3K/mTOR pathway, either through amplifications, deletions, or as a direct result of mutations, has been closely linked to the development and progression of a wide range of cancers. Moreover, this pathway activation is a poor prognostic marker for many tumor types and confers resistance to various cancer therapies. Here, we describe VS-5584, a novel, low-molecular weight compound with equivalent potent activity against mTOR (IC(50) = 37 nmol/L) and all class I phosphoinositide 3-kinase (PI3K) isoforms IC(50): PI3Kα = 16 nmol/L; PI3Kβ = 68 nmol/L; PI3Kγ = 25 nmol/L; PI3Kδ = 42 nmol/L, without relevant activity on 400 lipid and protein kinases. VS-5584 shows robust modulation of cellular PI3K/mTOR pathways, inhibiting phosphorylation of substrates downstream of PI3K and mTORC1/2. A large human cancer cell line panel screen (436 lines) revealed broad antiproliferative sensitivity and that cells harboring mutations in PI3KCA are generally more sensitive toward VS-5584 treatment. VS-5584 exhibits favorable pharmacokinetic properties after oral dosing in mice and is well tolerated. VS-5584 induces long-lasting and dose-dependent inhibition of PI3K/mTOR signaling in tumor tissue, leading to tumor growth inhibition in various rapalog-sensitive and -resistant human xenograft models. Furthermore, VS-5584 is synergistic with an EGF receptor inhibitor in a gastric tumor model. The unique selectivity profile and favorable pharmacologic and pharmaceutical properties of VS-5584 and its efficacy in a wide range of human tumor models supports further investigations of VS-5584 in clinical trials.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|VS-5584||SB-2343|SB2343|VS5584||mTOR Inhibitor 51 PI3K Inhibitor (Pan) 40||VS-5584 (SB-2343) inhibits mTOR kinase and all class I PI3K isoforms, disrupting phosphorylation of substrates downstream of PI3K and mTOR, thereby preventing cell proliferation and inhibiting tumor growth (PMID: 23270925, PMID: 32286946).|
|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 mutant||Advanced Solid Tumor||sensitive||VS-5584||Preclinical||Actionable||In preclinical studies, VS-5584 demonstrated efficacy in a variety of cancer cell lines, particularly those harboring PIK3CA mutations (PMID: 23270925).||23270925|
|PIK3CA E542K||colon adenocarcinoma||sensitive||VS-5584||Preclinical||Actionable||In preclinical studies, VS-5584 demonstrated efficacy in a variety of cancer cell lines, particularly those harboring PIK3CA mutations (PMID: 23270925).||23270925|
|FLT3 act mut||acute myeloid leukemia||sensitive||VS-5584||Preclinical - Cell line xenograft||Actionable||In a preclinical study, VS-5584 inhibited PI3K/mTOR signaling and cell proliferation in a FLT3-ITD positive human acute myeloid leukemia cell line in culture, and inhibited tumor growth in xenograft models (PMID: 23270925).||23270925|
|PTEN del||prostate cancer||sensitive||VS-5584||Preclinical - Cell line xenograft||Actionable||In a preclinical study, VS-5584 inhibited PI3K/mTOR signaling and cell proliferation in a human prostate cancer cell line harboring a PTEN deletion in culture, and inhibited PI3K/MTOR signaling and tumor growth in xenograft models (PMID: 23270925).||23270925|
|PIK3CA mutant||breast cancer||sensitive||VS-5584||Preclinical||Actionable||In a preclinical study, PIK3CA mutant breast cancer cells showed increased sensitivity to VS-5584 compared to PIK3CA wild-type cells in culture (PMID: 23270925).||23270925|