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

被引：41

作者：

Pei, Zhonghua ^{[1
]}

Blackwood, Elizabeth ^{[2
]}

Liu, Lichuan ^{[3
]}

Malek, Shiva ^{[4
]}

Belvin, Marcia ^{[2
]}

Koehler, Michael F. T. ^{[1
]}

Ortwine, Daniel F. ^{[1
]}

Chen, Huifen ^{[1
]}

Cohen, Frederick ^{[1
]}

Kenny, Jane R. ^{[3
]}

Bergeron, Philippe ^{[1
]}

Lau, Kevin ^{[1
]}

Ly, Cuong ^{[1
]}

Zhao, Xianrui ^{[1
]}

Estrada, Anthony A. ^{[1
]}

Tom Truong ^{[2
]}

Epler, Jennifer A. ^{[2
]}

Nonomiya, Jim ^{[4
]}

Lan Trinh ^{[4
]}

Sideris, Steve ^{[4
]}

Lesnick, John ^{[4
]}

Bao, Linda ^{[5
]}

Vijapurkar, Ulka ^{[2
]}

Mukadam, Sophie ^{[3
]}

Tay, Suzanne ^{[3
]}

Deshmukh, Gauri ^{[3
]}

Chen, Yung-Hsiang ^{[3
]}

Ding, Xiao ^{[3
]}

Friedman, Lori S. ^{[2
]}

Lyssikatos, Joseph P. ^{[1
]}

机构：

[1] Genentech Inc, Dept Discovery Chem, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept DMPK, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Pharmaceut, San Francisco, CA 94080 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 01期

关键词：

Mammalian target of rapamycin; mTOR; TDI; urea bioisostere; MECHANISM-BASED INACTIVATION; CYTOCHROME-P450; ENZYMES; GDC-0941; CANCER; KINASE;

D O I：

10.1021/ml3003132

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：103 / 107

页数：5

共 50 条

[41] CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization
Mortensen, Deborah S.
Fultz, Kimberly E.
Xu, Shuichan
Xu, Weiming
Packard, Garrick
Khambatta, Godrej
Gamez, James C.
Leisten, Jim
Zhao, Jingjing
Apuy, Julius
Ghoreishi, Kamran
Hickman, Matt
Narla, Rama Krishna
Bissonette, Rene
Richardson, Samantha
Peng, Sophie X.
Perrin-Ninkovic, Sophie
Tran, Tam
Shi, Tao
Yang, Wen Qing
Tong, Zeen
Cathers, Brian E.
Moghaddam, Mehran F.
Canan, Stacie S.
Worland, Peter
Sankar, Sabita
Raymon, Heather K.
MOLECULAR CANCER THERAPEUTICS, 2015, 14 (06) : 1295 - 1305
[42] Investigation of morpholine isosters for the development of a potent, selective and metabolically stable mTOR kinase inhibitor
De Pascale, Martina
Bissegger, Lukas
Tarantelli, Chiara
Beaufils, Florent
Prescimone, Alessandro
Hedad, Hayget Mohamed Seid
Kayali, Omar
Orbegozo, Clara
Raguz, Luka
Schaefer, Thorsten
Hebeisen, Paul
Bertoni, Francesco
Wymann, Matthias P.
Borsari, Chiara
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2023, 248
[43] Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR
Heffron, Timothy P.
Ndubaku, Chudi O.
Salphati, Laurent
Alicke, Bruno
Cheong, Jonathan
Drobnick, Joy
Edgar, Kyle
Gould, Stephen E.
Lee, Leslie B.
Lesnick, John D.
Lewis, Cristina
Nonomiya, Jim
Pang, Jodie
Plise, Emile G.
Sideris, Steve
Wallin, Jeffrey
Wang, Lan
Zhang, Xiaolin
Olivero, Alan G.
ACS MEDICINAL CHEMISTRY LETTERS, 2016, 7 (04): : 351 - 356
[44] Discovery of the potent PI3K/mTOR dual inhibitor PF-04979064
Cheng, Hengmiao
Bagrodia, Shubha
Bailey, Simon
Baxi, Sangita M.
Goulet, Lance
Guo, Lisa
Hoffman, Jacqui
Johnson, Ted O.
Johnson, Ted W.
Li, Chunze
Li, John
Liu, Kevin
Liu, Zhengyu
Marx, Matthew A.
Paderes, Gigi
Sun, Shaoxian
Walls, Marlena
Wells, Peter A.
Yang, Anle
Yin, Min-Jean
Zhu, Jingjiang
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2010, 240
[45] Discovery of clinical candidate GDC-0276: A selective NaV1.7 inhibitor for the treatment of pain
Sutherlin, Daniel
Sun, Shaoyi
Chowdhury, Sultan
Jia, Qi
Zenova, Alla
Wilson, Michael
Focken, Thilo
Li, Jun
Bichler, Paul
Decker, Shannon
Grimwood, Mike
Hemeon, Ivan
Sheng, Tao
Andrez, Jean-Christophe
Hackos, David
Bankar, Girish
Khakh, Kuldip
Chang, Elaine
Kwan, Rainbow
Lin, Sohia
Nelkenbrecher, Karen
Ortwine, Daniel
Chang, Jae
Pang, Jodie
Sojo, Luis
Chiang, Po-chang
Sambrone, Amy
Tagen, Michael
White, Andrew
Chen, Chien-An
Chen, John
Lovelidge, Jane
Ding, Xiao
Takahashi, Ryan
Waldbrook, Matthew
Xie, Zhiwei
Young, Clint
Robinette, Lee
Cohen, Charles
Oballa, Renata
Dehnhardt, Christoph
Safina, Brian
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2017, 254
[46] Discovery of OICR-10268: A potent and selective BCL6 inhibitor
Watson, Lain D.
Isaac, Methvin
Wilson, Brian
Anh Chau
Morin, Justin
Subramanian, Pandiaraju
Mamai, Ahmed
Joseph, Babu
Prakesch, Michael
Uehling, David
Abibi, Ayome
Marcellus, Richard
Strathdee, Craig
Subramaniam, Ratheesh
Theriault, Brigitte
Winston, Jeffrey
Chan, Manuel
Griffin, Carly
Cheung, Herman
Kiyota, Taira
Undzys, Elijus
Aman, Ahmed
Poda, Gennady
Kuntz, Doug
Pomroy, Neil C.
Prive, Gil G.
Al-awar, Rima
CANCER RESEARCH, 2019, 79 (13)
[47] Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor
Kim, Hyung-Gu
Tan, Li
Weisberg, Ellen L.
Liu, Feiyang
Canning, Peter
Choi, Hwan Geun
Ezell, Scott A.
Wu, Hong
Zhao, Zheng
Wang, Jinhua
Mandinova, Anna
Griffin, James D.
Bullock, Alex N.
Liu, Qingsong
Lee, Sam W.
Gray, Nathanael S.
ACS CHEMICAL BIOLOGY, 2013, 8 (10) : 2145 - 2150
[48] Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR
Petros, Andrew M.
Huth, Jeffrey R.
Oost, Thorsten
Park, Cheol-Min
Ding, Hong
Wang, Xilu
Zhang, Haichao
Nimmer, Paul
Mendoza, Renaldo
Sun, Chaohong
Mack, Jamey
Walter, Karl
Dorwin, Sarah
Gramling, Emily
Ladror, Uri
Rosenberg, Saul H.
Elmore, Steven W.
Fesik, Stephen W.
Hajduk, Philip J.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (22) : 6587 - 6591
[49] Discovery of DS-1971a, a Potent, Selective NaV1.7 Inhibitor
Shinozuka, Tsuyoshi
Kobayashi, Hiroyuki
Suzuki, Sayaka
Tanaka, Kyosuke
Karanjule, Narayan
Hayashi, Noriyuki
Tsuda, Toshifumi
Tokumaru, Eri
Inoue, Masahiro
Ueda, Kiyono
Kimoto, Hiroko
Domon, Yuki
Takahashi, Sakiko
Kubota, Kazufumi
Yokoyama, Tomihisa
Shimizugawa, Akiko
Koishi, Ryuta
Fujiwara, Chie
Asano, Daigo
Sakakura, Tomoko
Takasuna, Kiyoshi
Abe, Yasuyuki
Watanabe, Toshiyuki
Kitano, Yutaka
JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (18) : 10204 - 10220
[50] Discovery of PF-07220060, a potent and selective CDK4 inhibitor
Anders, Lars
Gallego, Gary
CANCER RESEARCH, 2024, 84 (07)

← 1 2 3 4 5 →