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Title: VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer
Authors: Hart, S.
Novotny-Diermayr, V.
Goh, K.C.
Williams, M.
Tan, Y.C.
Ong, L.C.
Cheong, A.
Ng, B.K.
Amalini, C.
Madan, B.
Nagaraj, H.
Jayaraman, R.
Pasha, K.M.
Ethirajulu, K.
Chng, W.J. 
Mustafa, N.
Goh, B.C. 
Benes, C.
McDermott, U.
Garnett, M.
Dymock, B.
Wood, J.M.
Issue Date: Feb-2013
Citation: Hart, S., Novotny-Diermayr, V., Goh, K.C., Williams, M., Tan, Y.C., Ong, L.C., Cheong, A., Ng, B.K., Amalini, C., Madan, B., Nagaraj, H., Jayaraman, R., Pasha, K.M., Ethirajulu, K., Chng, W.J., Mustafa, N., Goh, B.C., Benes, C., McDermott, U., Garnett, M., Dymock, B., Wood, J.M. (2013-02). VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer. Molecular Cancer Therapeutics 12 (2) : 151-161. ScholarBank@NUS Repository.
Abstract: 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 (IC50 = 37 nmol/L) and all class I phosphoinositide 3-kinase (PI3K) isoforms IC50: PI3Ka = 16 nmol/L; PI3Kβ = 68 nmol/L; PI3Kγ = 25 nmol/L; PI3Kσ = 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. © 2012 American Association for Cancer Research.
Source Title: Molecular Cancer Therapeutics
ISSN: 15357163
DOI: 10.1158/1535-7163.MCT-12-0466
Appears in Collections:Staff Publications

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