title: 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 sub-nanomolar IC50s against PI3Kα and PI3Kδ. BAY 80-6946 exhibited preferential inhibition (about 10-fold) of AKT phosphorylation by PI3Kα compared with PI3Kβ 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.
authors.affiliation: Corresponding Author: Ningshu Liu, Bayer HealthCare Pharmaceuticals, Muellerstr 178, Berlin 13342, Germany. ningshu.liu@bayer.com.
authors.forename: Ningshu
authors.initials: N
authors.lastname: Liu
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Rowley
authors.forename: Cathy O
authors.initials: CO
authors.lastname: Bull
authors.forename: Claudia
authors.initials: C
authors.lastname: Schneider
authors.forename: Andrea
authors.initials: A
authors.lastname: Haegebarth
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Schatz
authors.forename: Paul R
authors.initials: PR
authors.lastname: Fracasso
authors.forename: Dean P
authors.initials: DP
authors.lastname: Wilkie
authors.forename: Martin
authors.initials: M
authors.lastname: Hentemann
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wilhelm
authors.forename: William J
authors.initials: WJ
authors.lastname: Scott
authors.forename: Dominik
authors.initials: D
authors.lastname: Mumberg
authors.forename: Karl
authors.initials: K
authors.lastname: Ziegelbauer
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009374:Neoplasms, Experimental; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011923:Rats, Nude; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C000589253:copanlisib