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

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.

• Authors: 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 12 Issue 2 Pg. 151-61 (Feb 2013) ISSN: 1538-8514 [Electronic] United States
• PMID: 23270925 (Publication Type: Journal Article)
• Copyright: ©2012 AACR.

Chemical References

• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Purines
• VS-5584
• MTOR protein, human
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, enzymology)
• Disease Models, Animal
• Female
• Gastrointestinal Neoplasms (drug therapy, enzymology)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mice, SCID
• Morpholines (adverse effects, pharmacokinetics, pharmacology)
• Neoplasms (drug therapy, enzymology)
• PTEN Phosphohydrolase (deficiency)
• Phosphoinositide-3 Kinase Inhibitors
• Prostatic Neoplasms (drug therapy, enzymology)
• Protein Kinase Inhibitors (adverse effects, pharmacokinetics, pharmacology)
• Purines (adverse effects, pharmacokinetics, pharmacology)
• Signal Transduction
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Xenograft Model Antitumor Assays