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Identification and characterization of NVP-BKM120, an orally available pan class I PI3-Kinase inhibitor

Maira, Sauveur-Michel, Pecchi, Sabina, Huang, Alan, Burger, Matthew, Knapp, Mark, Sterker, Dario, Huh, Kay, Schnell, Christian, Guthy, Daniel Alexander, Nagel, Tobi, Wiesmann, Marion, Brachmann, Saskia, Fritsch, Christine, Dorsch, Marion, Chene, Patrick, Shoemaker, Kevin, De Pover, Alain, Menezes, Daniel, Fabbro, Doriano, Wilson, Christopher, garcia-echeverria, carlos, Schlegel, Robert, Sellers, William, Hofmann, Francesco and Voliva, Charles (2011) Identification and characterization of NVP-BKM120, an orally available pan class I PI3-Kinase inhibitor. Molecular Cancer Therapeutics, 11 (2). pp. 317-328. ISSN 1535-7163


The PI3K/Akt/mTor signaling pathway plays an important role in controlling cell growth, proliferation and survival. Following the discovery of NVP-BEZ235, our first dual pan-PI3K/mTOR clinical compound, we sought to identify additional PI3K inhibitors from different chemical classes with more stringent selectivity profiles. The key to achieve these objectives was to couple a structure-based design approach with intensive pharmacological evaluation of selected compounds during the medicinal chemistry optimization process. Here we report on the biological 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 (relative to p110) against other protein kinases. The compound is also active against the most common somatic PI3K 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. Moreover, NVP-BKM120 demonstrates synergistic advantages when combined with either targeted therapy agents such as MEK or HER2 inhibitors or with cytotoxic agents such as Docetaxel or Temozolomide. The pharmacological, biological and preclinical safety profile of NVP-BKM120 supports its clinical development and the compound is currently undergoing Phase II clinical trials in cancer patients.

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Additional Information: author can archive post-print (ie final draft post-refereeing); Authors final version may be deposited on institutional website/ repository if required by institution
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15


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