BAY 80-6946 Is a Highly Selective Intravenous PI3K Inhibitor with Potent p110α and p110δ Activities in Tumor Cell Lines and Xenograft Models

Abstract

Because of the complexity derived from the existence of various phosphoinositide 3-kinase (PI3K) isoforms and their differential roles in cancers, development of PI3K inhibitors with differential pharmacologic and pharmacokinetic profiles would allow best exploration in different indications, combinations, and dosing regimens. Here, we report BAY 80-6946, a highly selective and potent pan-class I PI3K inhibitor with subnanomolar IC 50 s against PI3Ka and PI3Kd. BAY 80-6946 exhibited preferential inhibition (about 10-fold) of AKT phosphorylation by PI3Ka compared with PI3Kb in cells. BAY 80-6946 showed superior antitumor activity (>40-fold) in PIK3CA mutant and/or HER2 overexpression as compared with HER2-negative and wild-type PIK3CA breast cancer cell lines. In addition, BAY 80-6946 revealed potent activity to induce apoptosis in a subset of tumor cells with aberrant activation of PI3K as a single agent. In vivo, single intravenous administration of BAY 80-6946 exhibited higher exposure and prolonged inhibition of pAKT levels in tumors versus plasma. BAY 80-6946 is efficacious in tumors with activated PI3K when dosed either continuously or intermittently. Thus, BAY 80-6946 induced 100% complete tumor regression when dosed as a single agent every second day in rats bearing HER2-amplified and PIK3CA-mutated KPL4 breast tumors. In combination with paclitaxel, weekly dosing of BAY 80-6946 is sufficient to reach sustained response in all animals bearing patient-derived non-small cell lung cancer xenografts, despite a short plasma elimination half-life (1 hour) in mice. Thus, BAY 80-6946 is a promising agent with differential pharmacologic and pharmacokinetic properties for the treatment of PI3K-dependent human tumors.

The PI3K Pathway in Human Disease

“…To this end, several groups are exploring alternative dosing strategies, particularly those involving high-dose, intermittent therapy as potential paths forward for the clinical applications of PI3K/mTOR pathway inhibitors. For example, the p110α/δ inhibitor copanlisib (BAY80-6946; Table S1), which has a half-life of only 0.7 hr after intravenous (IV) administration in mice, was far more effective in mice bearing BT474 breast cancer xenografts when administered intermittently (3 times per week) than when administered by continuous dosing (Liu et al, 2013). Similarly, intermittent dosing of the p110α/δ-selective inhibitor, AZD8835, was clearly superior to daily dosing of this drug in a preclinical breast cancer model (Hudson et al, 2016).…”

Detection and manipulation of phosphoinositides

“…Genetic studies suggest that the PI 3-kinase pathway is the most frequently altered pathway in human tumors, with the gene encoding the PI 3-kinase catalytic p110α subunit (PIK3CA) being the second most frequently mutated oncogene and PTEN being among the most frequently mutated tumor suppressor genes [66]. Drugs targeting this pathway are therefore attractive candidates for cancer treatment and several pan-PI3-kinase and isoform-selective inhibitors, such as BAY806946 (pan-PI 3-kinase), NVP-BYL719 (p110a) and GSK2636771 (p110β), are currently in clinical trials (reviewed elsewhere) [67,68]. The most impressive results have been achieved with the p110δ-selective inhibitor GS-1101 (idelalisib) in the treatment of chronic lymphocytic leukemia and other B-cell malignancies [69,70].…”

Mantle Cell Lymphoma: Individualizing Therapy

“…86 Two class I PI3K isoform inhibitors have been tested in the setting of relapsed MCL, the oral isoform-selective inhibitor PI3Kd (CAL-101/GS-1101, idelalisib), which blocks survival signals, induces apoptosis, and disrupts signals from the tumor microenvironment to B-cell malignancies, [87][88][89] and the more pleiotropic PI3Kα-d (copanlisib, BAY 80-6946), which exhibits preferential inhibition of AKT phosphorylation, superior antitumor activity, and potent apoptosis activity to induce apoptosis. 90 A phase I trial of idelalisib in heavily pretreated patients with MCL confirmed the activity of this compound with an ORR of 40% (5% CR) and a one-year PFS rate of 22%. 91 Copanlisib, which is administered intravenously, has been evaluated in a phase II study in patients with different lymphoma subtypes, including seven patients with MCL.…”