Abstract: Use of phospho-Akt as a biomarker for predicting the response, such as resistance, to a compound, wherein phospho-Akt is Akt that has been phosphorylated on one or more residues, with the proviso that for Akt1, Akt2, and Akt3 the designation phospho-Akt is used to indicate phosphorylation at a site other than T308, T309 or T305 respectively, wherein the compound is a compound of general formula (I).
Abstract: Expression of the polyoma middle T antigen (PyMT) or the HER2/Neu oncogene in the mammary gland of transgenic mice from MMTV LTR-driven expression constructs, gives rise to mammary adenocarcinomas. Here we show that ablation of Akt1 inhibits, while ablation of Akt2 accelerates tumor induction by both transgenes. The tumors arising in mice lacking individual Akt isoforms exhibit distinct histologic phenotypes. Although all these tumors are locally invasive however, they differ in metastatic potential, with the Akt1?/? tumors being less metastatic. The development of the mammary gland during puberty and the expression of MMTV LTR-driven transgenes in Akt1, Akt2 and Akt3 knockout mice are normal. These data combined, indicate that ablation of individual Akt isoforms influences tumor induction by modulating oncogenic signaling induced by the two transgenes.
Abstract: This application relates to methods of quantifying AKT1 and AKT2 and determining AKT1 and AKT2 phosphorylation status. The disclosed methods allow for selection of cancer therapy.
Abstract: The invention provides compositions and methods that modulate the activity of AKT family kinase proteins, including AKT1, AKT2 and AKT3 (also referred to as PKB?, PKB?and PKB?). Specifically, the invention provides a number of phenoxazine and acridone compounds that inhibit AKT phosphorylation and kinase activity. The invention provides compositions for and methods of modulating AKT activity, inhibiting cell growth, treating cancer, treating transplant rejection, and treating coronary artery disease based upon the phenoxazine and acridone compounds of the invention.
Type:
Application
Filed:
March 3, 2006
Publication date:
October 26, 2006
Applicant:
St. Jude Children's Research Hospital
Inventors:
Peter Houghton, Kuntebommenahalli Thimmaiah, John Easton
Abstract: The instant invention provides for substituted naphthyridine compounds that inhibit Akt activity. In particular, the compounds disclosed selectively inhibit one or two of the Akt isoforms, preferably Akt1. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting Akt activity especially Akt1 by administering the compound to a patient in need of treatment of cancer.
Type:
Application
Filed:
May 28, 2009
Publication date:
April 21, 2011
Inventors:
Hidetomo Furuyama, Yasuhiro Goto, Nobuhiko Kawanishi, Mark E. Layton, Takashi Mita, Akira Naya, Yoshio Ogino, Yu Onozaki, Kevin J. Rodzinak, Toshihiro Sakamoto, Philip E. Sanderson, Jiabing Wang
Abstract: Antisense compounds, compositions and methods are provided for modulating the expression of Akt-3. The compositions comprise antisense compounds, particulary antisense oligonucleotides, targeted to nucleic acids encoding Akt-3. Methods of using these compounds for modulations of Akt-3 expression and for treatment of diseases associated with expression of Akt-3 are provided.
Type:
Application
Filed:
June 21, 2002
Publication date:
August 7, 2003
Inventors:
Brett P. Monia, Lex M. Cowsert, Richard A. Roth
Abstract: Provided is use of a pharmaceutical composition in treating a glucocorticoid-resistant tumor characterized by an increased level of Akt2 expression. The pharmaceutical composition comprises an Akt2 inhibitor, a glucocorticoid, and optionally a pharmaceutically acceptable carrier, excipient and/or diluent. Also provided are use of an Akt2 detecting agent in detecting a glucocorticoid-resistant tumor, and use of an Akt2 inhibitor in the preparation of a pharmaceutical composition for treating a tumor.
Abstract: The instant invention provides for substituted [1,2,4]triazolo[4,3-a]-1,5-naphthyridine compounds that inhibit Akt activity. In particular, the compounds disclosed selectively inhibit one or two of the Akt isoforms, preferably Akt1. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting Akt activity, especially Akt1 by administering the compound to a patient in need of treatment of cancer.
Type:
Grant
Filed:
May 27, 2009
Date of Patent:
September 17, 2013
Assignees:
Merck Sharp & Dohme Corp., MSD K.K.
Inventors:
Hidetomo Furuyama, Yasuhiro Goto, Nobuhiko Kawanishi, Mark E. Layton, Takashi Mita, Yoshio Ogino, Yu Onozaki, Michael A. Rossi, Toshihiro Sakamoto, Philip E. Sanderson, Jiabing Wang
Abstract: Provided is use of a pharmaceutical composition in treating a glucocorticoid-resistant tumor characterized by an increased level of Akt2 expression. The pharmaceutical composition comprises an Akt2 inhibitor, a glucocorticoid, and optionally a pharmaceutically acceptable carrier, excipient and/or diluent. Also provided are use of an Akt2 detecting agent in detecting a glucocorticoid-resistant tumor, and use of an Akt2 inhibitor in the preparation of a pharmaceutical composition for treating a tumor.
Abstract: The instant invention provides for substituted [1,2,4]triazolo[4,3-a]-1,5-naphthyridine compounds that inhibit Akt activity. In particular, the compounds disclosed selectively inhibit one or two of the Akt isoforms, preferably Akt1. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting Akt activity, especially Akt1 by administering the compound to a patient in need of treatment of cancer.
Type:
Application
Filed:
May 27, 2009
Publication date:
April 7, 2011
Inventors:
Hidetomo Furuyama, Yasuhiro Goto, Nobuhiko Kawanishi, Mark E. Layton, Takashi Mita, Yoshio Ogino, Yu Onozaki, Michael A. Rossi, Toshihiro Sakamoto, Philip E. Sanderson, Jiabing Wang
Abstract: Disclosed herein is a species of peptide and non-peptide inhibitors of Akt, an oncogenic protein. Beginning with a residue of Akt target substrate GSK-3, the functional domains of the GSK-3 residue were characterized. Functionally homologous non-peptide groups were substituted for the amino acids of the GSK-3 creating a hybrid peptide-non-peptide and non-peptide compounds capable of binding to Akt. The non-peptide compounds show increased stability and rigidity compared to peptide counterparts and are less susceptible to degradation. The bound non-peptide compounds exhibit an inhibitory effect on Akt, similar to peptide-based Akt inhibitors.
Type:
Application
Filed:
August 30, 2016
Publication date:
December 22, 2016
Applicants:
University of South Florida, Yale University
Inventors:
Said M. Sebti, Jin Q. Cheng, Andrew D. Hamilton, Katherine Kayser-Bricker
Abstract: Antisense compounds, compositions and methods are provided for modulating the expression of Akt-1. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding Akt-1. Methods of using these compounds for modulation of Akt-1 expression and for treatment of diseases associated with expression of Akt-1 are provided.
Abstract: Disclosed are bifunctional compounds comprising a GDC-0068 analog that binds AKT isoforms AKT1, 2 and 3, pharmaceutical compositions, and methods for treating diseases or conditions mediated by dysfunctional AKT activity.
Type:
Application
Filed:
April 8, 2020
Publication date:
July 21, 2022
Applicants:
DANA-FARBER CANCER INSTITUTE, INC., BETH ISRAEL DEACONESS MEDICAL CENTER, INC.
Inventors:
Nathanael Gray, Inchul You, Tinghu Zhang, Eric Fischer, Katherine Donovan, Emily Erickson, Alex Toker
Abstract: Disclosed herein is a species of peptide and non-peptide inhibitors of Akt, an oncogenic protein. Beginning with a residue of Akt target substrate GSK-3, the functional domains of the GSK-3 residue were characterized. Functionally homologous non-peptide groups were substituted for the amino acids of the GSK-3 creating a hybrid peptide-non-peptide and non-peptide compounds capable of binding to Akt. The non-peptide compounds show increased stability and rigidity compared to peptide counterparts and are less susceptible to degradation. The bound non-peptide compounds exhibit an inhibitory effect on Akt, similar to peptide-based Akt inhibitors.
Type:
Grant
Filed:
June 8, 2009
Date of Patent:
September 2, 2014
Assignees:
University of South Florida, Yale University
Inventors:
Said M. Sebti, Jin Q. Cheng, Andrew D. Hamilton, Katherine Kayser-Bricker
Abstract: Antisense compounds, compositions and methods are provided for modulating the expression of Akt-3. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding Akt-3. Methods of using these compounds for modulation of Akt-3 expression and for treatment of diseases associated with expression of Akt-3 are provided.
Type:
Grant
Filed:
December 29, 1999
Date of Patent:
February 13, 2001
Assignee:
Isis Pharmaceuticals, Inc.
Inventors:
Brett P. Monia, Lex M. Cowsert, Richard A. Roth
Abstract: Antisense compounds, compositions and methods are provided for modulating the expression of Akt-2. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding Akt-2. Methods of using these compounds for modulation of Akt-2 expression and for treatment of diseases associated with expression of Akt-2 are provided.
Abstract: Disclosed herein is a species of peptide and non-peptide inhibitors of Akt, an oncogenic protein. Beginning with a residue of Akt target substrate GSK-3, the functional domains of the GSK-3 residue were characterized. Functionally homologous non-peptide groups were substituted for the amino acids of the GSK-3 creating a hybrid peptide-non-peptide and non-peptide compounds capable of binding to Akt. The non-peptide compounds show increased stability and rigidity compared to peptide counterparts and are less susceptible to degradation. The bound non-peptide compounds exhibit an inhibitory effect on Akt, similar to peptide-based Akt inhibitors.
Type:
Grant
Filed:
August 29, 2014
Date of Patent:
September 27, 2016
Assignees:
University of South Florida, Yale University
Inventors:
Said M. Sebti, Jin Q. Cheng, Andrew D. Hamilton, Katherine Kayser-Bricker
Abstract: Disclosed herein is a species of peptide and non-peptide inhibitors of Akt, an oncogenic protein. Beginning with a residue of Akt target substrate GSK-3, the functional domains of the GSK-3 residue were characterized. Functionally homologous non-peptide groups were substituted for the amino acids of the GSK-3 creating a hybrid peptide-non-peptide and non-peptide compounds capable of binding to Akt. The non-peptide compounds show increased stability and rigidity compared to peptide counterparts and are less susceptible to degradation. The bound non-peptide compounds exhibit an inhibitory effect on Akt, similar to peptide-based Akt inhibitors.
Type:
Application
Filed:
June 8, 2009
Publication date:
January 14, 2010
Applicants:
UNIVERSITY OF SOUTH FLORIDA, YALE UNIVERSITY
Inventors:
Said M. Sebti, Jin Q. Cheng, Andrew D. Hamilton, Katherine Kayser-Bricker
Abstract: Disclosed herein is a species of peptide and non-peptide inhibitors of Akt, an oncogenic protein. Beginning with a residue of Akt target substrate GSK-3, the functional domains of the GSK-3 residue were characterized. Functionally homologous non-peptide groups were substituted for the amino acids of the GSK-3 creating a hybrid peptide-non-peptide and non-peptide compounds capable of binding to Akt. The non-peptide compounds show increased stability and rigidity compared to peptide counterparts and are less susceptible to degradation. The bound non-peptide compounds exhibit an inhibitory effect on Akt, similar to peptide-based Akt inhibitors.
Type:
Grant
Filed:
August 30, 2016
Date of Patent:
February 20, 2018
Assignees:
University of South Florida, Yale University
Inventors:
Said M. Sebti, Jin Q. Cheng, Andrew D. Hamilton, Katherine Kayser-Bricker
Abstract: AKT/PKB kinase is a key signaling component of one of the most frequently activated pathways in cancer and is a major target of cancer drug development. The present study uncovered that growth factors binding to RTKs lead to activation of a non-receptor tyrosine kinase, Ack1 (TNK2), which directly phosphorylates AKT at a conserved tyrosine 176 residue. Tyr176-phosphorylated AKT binds to phosphatidic acid and localizes to the plasma membrane, leading to AKT activation. Expression levels of Tyr176-phosphorylated-AKT and Tyr284-phosphorylated-Ack1 were positively correlated with the severity of disease progression, and inversely correlated with the survival of breast, prostate, lung and pancreatic cancer patients.
Type:
Grant
Filed:
August 8, 2011
Date of Patent:
October 15, 2013
Assignee:
H. Lee Moffitt Cancer Center and Research Institute, Inc.