3SD5

Crystal Structure of PI3K gamma with 5-(2,4-dimorpholinopyrimidin-6-yl)-4-(trifluoromethyl)pyridin-2-amine

Summary for 3SD5

• Entry DOI: 10.2210/pdb3sd5/pdb
• Related: 3P2B
• Descriptor: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 5-[2,6-di(morpholin-4-yl)pyrimidin-4-yl]-4-(trifluoromethyl)pyridin-2-amine (3 entities in total)
• Functional Keywords: lipid kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P48736
• Total number of polymer chains: 1
• Total formula weight: 111166.56

Authors

Knapp, M.S.,Elling, R.A. (deposition date: 2011-06-08, release date: 2012-01-04, Last modification date: 2023-09-13)

Primary citation

Maira, S.M.,Pecchi, S.,Huang, A.,Burger, M.,Knapp, M.,Sterker, D.,Schnell, C.,Guthy, D.,Nagel, T.,Wiesmann, M.,Brachmann, S.,Fritsch, C.,Dorsch, M.,Chene, P.,Shoemaker, K.,De Pover, A.,Menezes, D.,Martiny-Baron, G.,Fabbro, D.,Wilson, C.J.,Schlegel, R.,Hofmann, F.,Garcia-Echeverria, C.,Sellers, W.R.,Voliva, C.F.
Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor.
Mol.Cancer Ther., 11:317-328, 2012

PubMed 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.

PubMed: 22188813
DOI: 10.1158/1535-7163.MCT-11-0474

Experimental method

X-RAY DIFFRACTION (3.2 Å)