title: Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor.
abstract: Following the discovery of NVP-BEZ235, our first dual pan-PI3K/mTOR clinical compound, we sought to identify additional phosphoinositide 3-kinase (PI3K) inhibitors from different chemical classes with a different selectivity profile. The key to achieve these objectives was to couple a structure-based design approach with intensive pharmacologic evaluation of selected compounds during the medicinal chemistry optimization process. Here, we report on the biologic characterization of the 2-morpholino pyrimidine derivative pan-PI3K inhibitor NVP-BKM120. This compound inhibits all four class I PI3K isoforms in biochemical assays with at least 50-fold selectivity against other protein kinases. The compound is also active against the most common somatic PI3Kα mutations but does not significantly inhibit the related class III (Vps34) and class IV (mTOR, DNA-PK) PI3K kinases. Consistent with its mechanism of action, NVP-BKM120 decreases the cellular levels of p-Akt in mechanistic models and relevant tumor cell lines, as well as downstream effectors in a concentration-dependent and pathway-specific manner. Tested in a panel of 353 cell lines, NVP-BKM120 exhibited preferential inhibition of tumor cells bearing PIK3CA mutations, in contrast to either KRAS or PTEN mutant models. NVP-BKM120 shows dose-dependent in vivo pharmacodynamic activity as measured by significant inhibition of p-Akt and tumor growth inhibition in mechanistic xenograft models. NVP-BKM120 behaves synergistically when combined with either targeted agents such as MEK or HER2 inhibitors or with cytotoxic agents such as docetaxel or temozolomide. The pharmacological, biologic, and preclinical safety profile of NVP-BKM120 supports its clinical development and the compound is undergoing phase II clinical trials in patients with cancer.
authors.affiliation: Novartis Institute for Biomedical Research, Oncology Disease Area, Novartis Pharma AG, Klybeckstrasse 141, CH-4002 Basel, Switzerland. sauveur-michel.maira@novartis.com
authors.forename: Sauveur-Michel
authors.initials: SM
authors.lastname: Maira
authors.forename: Sabina
authors.initials: S
authors.lastname: Pecchi
authors.forename: Alan
authors.initials: A
authors.lastname: Huang
authors.forename: Matthew
authors.initials: M
authors.lastname: Burger
authors.forename: Mark
authors.initials: M
authors.lastname: Knapp
authors.forename: Dario
authors.initials: D
authors.lastname: Sterker
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.forename: Daniel
authors.initials: D
authors.lastname: Guthy
authors.forename: Tobi
authors.initials: T
authors.lastname: Nagel
authors.forename: Marion
authors.initials: M
authors.lastname: Wiesmann
authors.forename: Saskia
authors.initials: S
authors.lastname: Brachmann
authors.forename: Christine
authors.initials: C
authors.lastname: Fritsch
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
authors.forename: Patrick
authors.initials: P
authors.lastname: Chène
authors.forename: Kevin
authors.initials: K
authors.lastname: Shoemaker
authors.forename: Alain
authors.initials: A
authors.lastname: De Pover
authors.forename: Daniel
authors.initials: D
authors.lastname: Menezes
authors.forename: Georg
authors.initials: G
authors.lastname: Martiny-Baron
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wilson
authors.forename: Robert
authors.initials: R
authors.lastname: Schlegel
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Echeverría
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Charles F
authors.initials: CF
authors.lastname: Voliva
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D007527:Isoenzymes; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt