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Literature DB >> 24900569

Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349.

Zhonghua Pei¹, Elizabeth Blackwood¹, Lichuan Liu¹, Shiva Malek¹, Marcia Belvin¹, Michael F T Koehler¹, Daniel F Ortwine¹, Huifen Chen¹, Frederick Cohen¹, Jane R Kenny¹, Philippe Bergeron¹, Kevin Lau¹, Cuong Ly¹, Xianrui Zhao¹, Anthony A Estrada¹, Tom Truong¹, Jennifer A Epler¹, Jim Nonomiya¹, Lan Trinh¹, Steve Sideris¹, John Lesnick¹, Linda Bao¹, Ulka Vijapurkar¹, Sophie Mukadam¹, Suzanne Tay¹, Gauri Deshmukh¹, Yung-Hsiang Chen¹, Xiao Ding¹, Lori S Friedman¹, Joseph P Lyssikatos¹.

Abstract

Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been observed in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization of advanced lead 1 culminated in the discovery of clinical development candidate 8h, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.

Entities: Chemical Disease Gene Species

Keywords: Mammalian target of rapamycin; TDI; mTOR; urea bioisostere

Year: 2012 PMID： 24900569 PMCID： PMC4027466 DOI： 10.1021/ml3003132

Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345

19 in total

Review 1. Drugging the PI3 kinome: from chemical tools to drugs in the clinic.

Authors: Paul Workman; Paul A Clarke; Florence I Raynaud; Rob L M van Montfort
Journal: Cancer Res Date: 2010-02-23 Impact factor: 12.701

Review 2. Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions.

Authors: Amit S Kalgutkar; R Scott Obach; Tristan S Maurer
Journal: Curr Drug Metab Date: 2007-06 Impact factor: 3.731

3. The discovery and optimisation of pyrido[2,3-d]pyrimidine-2,4-diamines as potent and selective inhibitors of mTOR kinase.

Authors: Karine Malagu; Heather Duggan; Keith Menear; Marc Hummersone; Sylvie Gomez; Christine Bailey; Peter Edwards; Jan Drzewiecki; Frédéric Leroux; Mar Jimenez Quesada; Gesine Hermann; Stephanie Maine; Carrie-Anne Molyneaux; Armelle Le Gall; James Pullen; Ian Hickson; Lisa Smith; Sharon Maguire; Niall Martin; Graeme Smith; Martin Pass
Journal: Bioorg Med Chem Lett Date: 2009-08-13 Impact factor: 2.823

4. mTOR Mediated Anti-Cancer Drug Discovery.

Authors: Qingsong Liu; Carson Thoreen; Jinhua Wang; David Sabatini; Nathanael S Gray
Journal: Drug Discov Today Ther Strateg Date: 2009

Review 5. Rapamycin passes the torch: a new generation of mTOR inhibitors.

Authors: Don Benjamin; Marco Colombi; Christoph Moroni; Michael N Hall
Journal: Nat Rev Drug Discov Date: 2011-10-31 Impact factor: 84.694

6. Imidazo[1,5-a]pyrazines: orally efficacious inhibitors of mTORC1 and mTORC2.

Authors: Andrew P Crew; Shripad V Bhagwat; Hanqing Dong; Mark A Bittner; Anna Chan; Xin Chen; Heather Coate; Andrew Cooke; Prafulla C Gokhale; Ayako Honda; Meizhong Jin; Jennifer Kahler; Christine Mantis; Mark J Mulvihill; Paula A Tavares-Greco; Brian Volk; Jing Wang; Douglas S Werner; Lee D Arnold; Jonathan A Pachter; Robert Wild; Neil W Gibson
Journal: Bioorg Med Chem Lett Date: 2011-02-03 Impact factor: 2.823

7. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition.

Authors: Klaus P Hoeflich; Mark Merchant; Christine Orr; Jocelyn Chan; Doug Den Otter; Leanne Berry; Ian Kasman; Hartmut Koeppen; Ken Rice; Nai-Ying Yang; Stefan Engst; Stuart Johnston; Lori S Friedman; Marcia Belvin
Journal: Cancer Res Date: 2011-11-14 Impact factor: 12.701

Review 8. Defining the role of mTOR in cancer.

Authors: David A Guertin; David M Sabatini
Journal: Cancer Cell Date: 2007-07 Impact factor: 31.743

9. Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors.

Authors: Arie Zask; Joshua Kaplan; Jeroen C Verheijen; David J Richard; Kevin Curran; Natasja Brooijmans; Eric M Bennett; Lourdes Toral-Barza; Irwin Hollander; Semiramis Ayral-Kaloustian; Ker Yu
Journal: J Med Chem Date: 2009-12-24 Impact factor: 7.446

10. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer .

Authors: Adrian J Folkes; Khatereh Ahmadi; Wendy K Alderton; Sonia Alix; Stewart J Baker; Gary Box; Irina S Chuckowree; Paul A Clarke; Paul Depledge; Suzanne A Eccles; Lori S Friedman; Angela Hayes; Timothy C Hancox; Arumugam Kugendradas; Letitia Lensun; Pauline Moore; Alan G Olivero; Jodie Pang; Sonal Patel; Giles H Pergl-Wilson; Florence I Raynaud; Anthony Robson; Nahid Saghir; Laurent Salphati; Sukhjit Sohal; Mark H Ultsch; Melanie Valenti; Heidi J A Wallweber; Nan Chi Wan; Christian Wiesmann; Paul Workman; Alexander Zhyvoloup; Marketa J Zvelebil; Stephen J Shuttleworth
Journal: J Med Chem Date: 2008-09-25 Impact factor: 7.446

7 in total

1. 3D-QSAR, molecular dynamics simulations, and molecular docking studies on pyridoaminotropanes and tetrahydroquinazoline as mTOR inhibitors.

Authors: Udit Chaube; Hardik Bhatt
Journal: Mol Divers Date: 2017-06-02 Impact factor: 2.943

Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349.

Review 1. Drugging the PI3 kinome: from chemical tools to drugs in the clinic.

Review 2. Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions.

3. The discovery and optimisation of pyrido[2,3-d]pyrimidine-2,4-diamines as potent and selective inhibitors of mTOR kinase.

4. mTOR Mediated Anti-Cancer Drug Discovery.

Review 5. Rapamycin passes the torch: a new generation of mTOR inhibitors.

6. Imidazo[1,5-a]pyrazines: orally efficacious inhibitors of mTORC1 and mTORC2.

7. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition.

Review 8. Defining the role of mTOR in cancer.

9. Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors.

10. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer .

1. 3D-QSAR, molecular dynamics simulations, and molecular docking studies on pyridoaminotropanes and tetrahydroquinazoline as mTOR inhibitors.

2. PIK3CA-mutated melanoma cells rely on cooperative signaling through mTORC1/2 for sustained proliferation.

3. Assessment of mitophagy in human iPSC-derived cardiomyocytes.

4. Virtual Screening and Optimization of Novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma.

Review 5. Overview of Research into mTOR Inhibitors.

6. High-throughput screen to identify compounds that prevent or target telomere loss in human cancer cells.

7. GDC-0349 inhibits non-small cell lung cancer cell growth.