title: Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor.
abstract: Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.
authors: Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: Melissa
authors: M
authors: Dumble
authors: Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: Ming-Chih
authors: MC
authors: Crouthamel
authors: Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: Shu-Yun
authors: SY
authors: Zhang
authors: Platform Technology & Science, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: Michael
authors: M
authors: Schaber
authors: Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: Dana
authors: D
authors: Levy
authors: Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: Kimberly
authors: K
authors: Robell
authors: Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: Qi
authors: Q
authors: Liu
authors: Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: David J
authors: DJ
authors: Figueroa
authors: Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: Elisabeth A
authors: EA
authors: Minthorn
authors: Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: Mark A
authors: MA
authors: Seefeld
authors: Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: Meagan B
authors: MB
authors: Rouse
authors: Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: Sridhar K
authors: SK
authors: Rabindran
authors: Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: Dirk A
authors: DA
authors: Heerding
authors: Oncology R & D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors: Rakesh
authors: R
authors: Kumar
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D003959:Diamines / Q000138:chemical synthesis / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001786:Blood Glucose; D003959:Diamines; D020930:MAP Kinase Kinase Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D019893:Ribosomal Protein S6 Kinases; C000595148:GSK2110183; C000595149:GSK2141795; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C491754:AKT3 protein, human; C494929:PTEN protein, human