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  • VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer.

VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer.

Molecular cancer therapeutics (2012-12-29)
Stefan Hart, Veronica Novotny-Diermayr, Kee Chuan Goh, Meredith Williams, Yong Cheng Tan, Lai Chun Ong, Albert Cheong, Bee Kheng Ng, Chithra Amalini, Babita Madan, Harish Nagaraj, Ramesh Jayaraman, Khalid M Pasha, Kantharaj Ethirajulu, Wee Joo Chng, Nurulhuda Mustafa, Boon Cher Goh, Cyril Benes, Ultan McDermott, Mathew Garnett, Brian Dymock, Jeanette M Wood
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 (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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Actin antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
VS-5584, ≥98% (HPLC)