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 PI3Ka 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 concentrationdependent 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. Mol Cancer Ther; 11(2); 317-28. Ó2011 AACR.

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245408 (XL147), an Oral Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors

“…preclinical studies have suggested that PIK3CA mutations might predict sensitivity to pan-PI3K and dual PI3K/mTOR inhibitors (25); however, these results have not yet been clinically validated. In contrast, studies with a-isoformselective and b-isoform-sparing PI3K inhibitors have produced responses among patients with tumors harboring PIK3CA mutations (26,27); in addition, the presence of a PIK3CA mutation-related gene signature may identify patients with breast cancer who may benefit from the addition of everolimus to letrozole (28), although clinical benefit from everolimus is not restricted to patients with PIK3CA-mutant tumors.…”

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

“…AMPK, AMP-dependent protein kinase; GF, growth factor; GRB2, growth factor receptor-bound protein 2; IRS1, insulin receptor substrate 1; PDK1, phosphoinositide-dependent kinase 1; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate. (Continued on the following page) (6,7), and no clinical responses with these compounds have been observed in patients with PTEN-altered tumors in single-agent phase I trials (8,9). In contrast, 1 of the 2 patients who experienced a partial response in the phase I single-agent trial of BEZ235 had non-small cell lung cancer (NSCLC) with PTEN mutation (10).…”

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

“…Buparlisib has demonstrated antiproliferative, proapoptotic, and antiangiogenic activity in multiple preclinical cancer models [46]. Buparlisib demonstrates synergistic activity with cytotoxic and targeted agents [46,47], and enhances sensitivity to these drugs in resistant cancer models [48].…”