title: The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models.
abstract: Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents.
authors: Exelixis, Inc., South San Francisco, California.
authors: Paul
authors: P
authors: Foster
authors: Exelixis, Inc., South San Francisco, California.
authors: Kyoko
authors: K
authors: Yamaguchi
authors: Exelixis, Inc., South San Francisco, California.
authors: Pin P
authors: PP
authors: Hsu
authors: Exelixis, Inc., South San Francisco, California.
authors: Fawn
authors: F
authors: Qian
authors: Exelixis, Inc., South San Francisco, California.
authors: Xiangnan
authors: X
authors: Du
authors: Exelixis, Inc., South San Francisco, California.
authors: Jianming
authors: J
authors: Wu
authors: Exelixis, Inc., South San Francisco, California.
authors: Kwang-Ai
authors: KA
authors: Won
authors: Exelixis, Inc., South San Francisco, California.
authors: Peiwen
authors: P
authors: Yu
authors: Exelixis, Inc., South San Francisco, California.
authors: Christopher T
authors: CT
authors: Jaeger
authors: Exelixis, Inc., South San Francisco, California.
authors: Wentao
authors: W
authors: Zhang
authors: Exelixis, Inc., South San Francisco, California.
authors: Charles K
authors: CK
authors: Marlowe
authors: Exelixis, Inc., South San Francisco, California.
authors: Paul
authors: P
authors: Keast
authors: Exelixis, Inc., South San Francisco, California.
authors: Wendy
authors: W
authors: Abulafia
authors: Exelixis, Inc., South San Francisco, California.
authors: Jason
authors: J
authors: Chen
authors: Exelixis, Inc., South San Francisco, California.
authors: Jenny
authors: J
authors: Young
authors: Exelixis, Inc., South San Francisco, California.
authors: Artur
authors: A
authors: Plonowski
authors: Exelixis, Inc., South San Francisco, California.
authors: F Michael
authors: FM
authors: Yakes
authors: Exelixis, Inc., South San Francisco, California.
authors: Felix
authors: F
authors: Chu
authors: Exelixis, Inc., South San Francisco, California.
authors: Kelly
authors: K
authors: Engell
authors: Exelixis, Inc., South San Francisco, California.
authors: Frauke
authors: F
authors: Bentzien
authors: Exelixis, Inc., South San Francisco, California.
authors: Sanh T
authors: ST
authors: Lam
authors: Exelixis, Inc., South San Francisco, California.
authors: Stephanie
authors: S
authors: Dale
authors: Exelixis, Inc., South San Francisco, California.
authors: Olivia
authors: O
authors: Yturralde
authors: Exelixis, Inc., South San Francisco, California.
authors: David J
authors: DJ
authors: Matthews
authors: Exelixis, Inc., South San Francisco, California.
authors: Peter
authors: P
authors: Lamb
authors: Exelixis, Inc., South San Francisco, California. douglaslaird2000@yahoo.com.
authors: A Douglas
authors: AD
authors: Laird
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; C581157:XL147; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases