title: GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway.
abstract: Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog (PTEN), and deregulation of mammalian target of rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. GDC-0980 potently inhibits signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 was potent across a broad panel of cancer cell lines, with the greatest potency in breast, prostate, and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistance markers. Treatment of cancer cell lines with GDC-0980 resulted in G1 cell-cycle arrest, and in contrast to mTOR inhibitors, GDC-0980 induced apoptosis in certain cancer cell lines, including those with direct pathway activation via PI3K and PTEN. Low doses of GDC-0980 potently inhibited tumor growth in xenograft models including those with activated PI3K, loss of LKB1 or PTEN, and elicited an exposure-related decrease in PD biomarkers. These preclinical data show that GDC-0980 is a potent and effective dual PI3K/mTOR inhibitor with promise for the clinic.
authors: Department of Translational Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
authors: Jeffrey J
authors: JJ
authors: Wallin
authors: Kyle A
authors: KA
authors: Edgar
authors: Jane
authors: J
authors: Guan
authors: Megan
authors: M
authors: Berry
authors: Wei Wei
authors: WW
authors: Prior
authors: Leslie
authors: L
authors: Lee
authors: John D
authors: JD
authors: Lesnick
authors: Cristina
authors: C
authors: Lewis
authors: Jim
authors: J
authors: Nonomiya
authors: Jodie
authors: J
authors: Pang
authors: Laurent
authors: L
authors: Salphati
authors: Alan G
authors: AG
authors: Olivero
authors: Daniel P
authors: DP
authors: Sutherlin
authors: Carol
authors: C
authors: O'Brien
authors: Jill M
authors: JM
authors: Spoerke
authors: Sonal
authors: S
authors: Patel
authors: Letitia
authors: L
authors: Lensun
authors: Robert
authors: R
authors: Kassees
authors: Leanne
authors: L
authors: Ross
authors: Mark R
authors: MR
authors: Lackner
authors: Deepak
authors: D
authors: Sampath
authors: Marcia
authors: M
authors: Belvin
authors: Lori S
authors: LS
authors: Friedman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008962:Models, Theoretical; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000145:classification / Q000378:metabolism / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000145:classification / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; C546842:MTOR protein, human