title: 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.affiliation: S*BIO Pte Ltd., Singapore 117528, Singapore. stefan.sbio@gmail.com
authors.forename: Stefan
authors.initials: S
authors.lastname: Hart
authors.forename: Veronica
authors.initials: V
authors.lastname: Novotny-Diermayr
authors.forename: Kee Chuan
authors.initials: KC
authors.lastname: Goh
authors.forename: Meredith
authors.initials: M
authors.lastname: Williams
authors.forename: Yong Cheng
authors.initials: YC
authors.lastname: Tan
authors.forename: Lai Chun
authors.initials: LC
authors.lastname: Ong
authors.forename: Albert
authors.initials: A
authors.lastname: Cheong
authors.forename: Bee Kheng
authors.initials: BK
authors.lastname: Ng
authors.forename: Chithra
authors.initials: C
authors.lastname: Amalini
authors.forename: Babita
authors.initials: B
authors.lastname: Madan
authors.forename: Harish
authors.initials: H
authors.lastname: Nagaraj
authors.forename: Ramesh
authors.initials: R
authors.lastname: Jayaraman
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Pasha
authors.forename: Kantharaj
authors.initials: K
authors.lastname: Ethirajulu
authors.forename: Wee Joo
authors.initials: WJ
authors.lastname: Chng
authors.forename: Nurulhuda
authors.initials: N
authors.lastname: Mustafa
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
authors.forename: Cyril
authors.initials: C
authors.lastname: Benes
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.forename: Mathew
authors.initials: M
authors.lastname: Garnett
authors.forename: Brian
authors.initials: B
authors.lastname: Dymock
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: Wood
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology; D004195:Disease Models, Animal; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009025:Morpholines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D051059:PTEN Phosphohydrolase / Q000172:deficiency; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011687:Purines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011687:Purines; C585120:VS-5584; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human