VS-5584, a Novel and Highly Selective PI3K/mTOR Kinase Inhibitor for the Treatment of Cancer
| Autor: | Jeanette Marjorie Wood, Ramesh Jayaraman, Yong Cheng Tan, Stefan Hart, Khalis M Pasha, Veronica Novotny-Diermayr, Albert Cheong, Kantharaj Ethirajulu, Nurulhuda Mustafa, B. K. Ng, Lai Chun Ong, Boon Cher Goh, Chithra Amalini, Wee Joo Chng, Babita Madan, Ultan McDermott, Meredith Williams, Harish Kumar Mysore Nagaraj, Kee Chuan Goh, Brian W. Dymock, Cyril H. Benes, Mathew J. Garnett |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Cancer Research Morpholines Mice Nude mTORC1 Mice SCID Biology Article Mice Cell Line Tumor Neoplasms medicine Animals Humans Receptor Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Cell Proliferation Gastrointestinal Neoplasms Phosphoinositide-3 Kinase Inhibitors Mice Inbred BALB C Kinase TOR Serine-Threonine Kinases PTEN Phosphohydrolase Cancer Prostatic Neoplasms medicine.disease Xenograft Model Antitumor Assays Disease Models Animal Oncology Biochemistry Cell culture Purines Cancer research Phosphorylation Female Signal transduction Colorectal Neoplasms Signal Transduction |
| Popis: | 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: 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. Mol Cancer Ther; 12(2); 151–61. ©2012 AACR. |
| Databáze: | OpenAIRE |
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