VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer
Menée sur des lignées cellulaires et à l'aide de xénogreffes de divers types de cancer, cette étude évalue l'activité antitumorale d'un composé appelé VS-5584, un inhibiteur de la signalisation PI3K/mTOR
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 nM) and all class I PI3K isoforms IC50: PI3Kα = 16 nM; PI3Kβ = 68 nM; PI3Kγ= 25 nM; PI3Kδ= 42 nM), 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 anti-proliferative sensitivity and that cells harboring mutations in PI3KCA are generally more sensitive towards 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 rapalogue-sensitive and -resistant human xenograft models. Furthermore, VS-5584 is synergistic with an EGFRi in a gastric tumor model. The unique selectivity profile and favorable pharmacological 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.
http://mct.aacrjournals.org/content/early/2012/12/27/1535-7163.MCT-12-0466.abstract