Discovery of Highly Potent, Selective, and Efficacious Small Molecule Inhibitors of ERK1/2

被引：30

作者：

Ren, Li ^{[1
]}

Grina, Jonas ^{[1
]}

Moreno, David ^{[1
]}

Blake, James F. ^{[1
]}

Gaudino, John J. ^{[1
]}

Garrey, Rustam ^{[1
]}

Metcalf, Andrew T. ^{[1
]}

Burkard, Michael ^{[1
]}

Martinson, Matthew ^{[1
]}

Rasor, Kevin ^{[1
]}

Chen, Huifen ^{[2
]}

Dean, Brian ^{[2
]}

Gould, Stephen E. ^{[2
]}

Pacheco, Patricia ^{[2
]}

Shahidi-Latham, Sheerin ^{[2
]}

Yin, Jianping ^{[2
]}

West, Kristina ^{[2
]}

Wang, Weiru ^{[2
]}

Moffat, John G. ^{[2
]}

Schwarz, Jacob B. ^{[2
]}

机构：

[1] Array BioPharma Inc, Boulder, CO 80301 USA

[2] Genentech Inc, San Francisco, CA 94080 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 04期

关键词：

ACQUIRED-RESISTANCE; PATHWAY; BRAF; KINASES;

D O I：

10.1021/jm501921k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Using structure-based design, a novel series of pyridone ERK1/2 inhibitors was developed. Optimization led to the identification of (S)-14k, a potent, selective, and orally bioavailable agent that inhibited tumor growth in mouse xenograft models. On the basis of its in vivo efficacy and preliminary safety profiles, (S)-14k was selected for further preclinical evaluation.

引用

页码：1976 / 1991

页数：16

共 50 条

[1] Discovery of potent and selective inhibitors of ERK1/2 with a unique mechanism of action
Deng, Yongqi
Samatar, Ahmed
Shipps, Gerald
Cooper, Alan
Long, Brian
Carr, Donnar
Xiao, Li
Hruza, Alan
Wang, Tong
Zhu, Liang
Nan, Yang
Patel, Mehul
Muppalla, Kiran
Zhu, Hugh
Boga, Babu Sobhana
Gao, Xiaolei
[J]. CANCER RESEARCH, 2016, 76
[2] Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor
Liu, K
Xu, LB
Szalkowski, D
Li, ZH
Ding, V
Kwei, G
Huskey, S
Moller, DE
Heck, JV
Zhang, BB
Jones, AB
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (19) : 3487 - 3494
[3] Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2
Ward, Richard A.
Coldough, Nicola
Challinor, Mairi
Debreczeni, Judit E.
Eckersley, Kay
Fairley, Gary
Feron, Lyman
Flemington, Vildd
Graham, Mark A.
Greenwood, Ryan
Hoperoft, Philip
Howard, Tina D.
James, Michael
Jones, Clifford D.
Jones, Christopher R.
Renshaw, Jonathan
Roberts, Karen
Snow, Lindsay
Tonge, Michael
Yeung, Kay
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (11) : 4790 - 4801
[4] Discovery of highly potent small molecule kallikrein inhibitors
Zhang, J.
Kirshnan, R.
Arnold, C. S.
Mattsson, E.
Kilpatrick, J. M.
Bantia, S.
Dehghani, A.
Boudreaux, B.
Gupta, S. N.
Kotian, P. L.
Chand, P.
Babu, Y. S.
[J]. MOLECULAR IMMUNOLOGY, 2007, 44 (1-3) : 263 - 263
[5] Discovery and synthesis of highly potent and selective small molecule inhibitors of the histone methyltransferase EZH2
Verma, Sharad K.
LaFrance, Louis V.
Tian, Xinrong
Newlander, Ken
Duguenne, Celine
Suarez, Dominic
Knight, Steven D.
Burgess, Joelle
Brackley, James
Johnson, Neil W.
Graves, Alan R.
Mellinger, Mark
Romeril, Stuart
Grant, Seth W.
Scherzer, Daryl
Shu, Art
Creasy, Caretha L.
Kruger, Ryan
Diaz, Elsie
Le, Baochau
Thompson, Christine
Morgan-Ott, Heidi
McCabe, Michael T.
McHugh, Charles F.
Miller, William H.
Tummino, Peter
Dhanak, Dash
[J]. CANCER RESEARCH, 2012, 72
[6] Discovery and characterization of AZ6197, a potent and selective ERK1/2 inhibitor
Flemington, Vikki
Simpson, Iain
Davies, Emma
Robinson, David
Lindsay, Nicola
Hanson, Lyndsey
Hopcroft, Philip
Tonge, Michael
Roberts, Karen
Ward, Richard
[J]. MOLECULAR CANCER THERAPEUTICS, 2018, 17 (01)
[7] Discovery of AZD0364, a potent and selective oral inhibitor of ERK1/2 that is efficacious in both monotherapy and combination therapy in models of NSCLC
Simpson, Iain
Anderton, Mark J.
Andrews, David M.
Breed, Jason
Davies, Emma
Debreczeni, Judit E.
Flemington, Vikki
Gibbons, Francis D.
Graham, Mark A.
Hopcroft, Philip
Howard, Tina
Hudson, Julian
Jones, Clifford D.
Jones, Christopher
Lindsay, Nicola
Pease, J. Elizabeth
Rawlins, Philip
Roberts, Karen
Swallow, Steve
St-Gallay, Steve
Tonge, Michael E.
Ward, Richard A.
[J]. CANCER RESEARCH, 2018, 78 (13)
[8] Discovery of Potent, Highly Selective, and In Vivo Efficacious, Allosteric MALT1 Inhibitors by Iterative Scaffold Morphing
Soldermann, Carole Pissot
Simic, Oliver
Renatus, Martin
Erbel, Paulus
Melkko, Samu
Wartmann, Markus
Bigaud, Marc
Weiss, Andreas
McSheehy, Paul
Endres, Ralf
Santos, Paulo
Blank, Jutta
Schuffenhauer, Ansgar
Bold, Guido
Buschmann, Nicole
Zoller, Thomas
Altmann, Eva
Manley, Paul W.
Dix, Ina
Buchdunger, Elisabeth
Scesa, Julien
Quancard, Jean
Schlapbach, Achim
Bornancin, Frederic
Radimerski, Thomas
Regnier, Catherine H.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (23) : 14576 - 14593
[9] Fragment-based discovery of a highly potent, orally bioavailable ERK1/2 inhibitor that modulates the phosphorylation and catalytic activity of ERK1/2
Heightman, Tom D.
Berdini, Valerio
Braithwaite, Hannah
Buck, Ildiko
Cassidy, Megan
Castro, Juan
Courtin, Aurelie
Day, James
East, Charlotte
Fazal, Lynsey
Graham, Brent
Griffiths-Jones, Charlotte
Lyons, John
Martins, Vanessa
Muench, Sandra
Munck, Joanne
Norton, David
O'Reilly, Marc
Palmer, Nick
Pathuri, Puja
Reader, Mike
Rees, David
Rich, Sharna
Richardson, Caroline
Saini, Harpreet
Thompson, Neil
Wallis, Nicola
Walton, Hugh
Wilsher, Nicola
Woolford, Alison
Murray, Chris
[J]. MOLECULAR CANCER THERAPEUTICS, 2018, 17 (01)
[10] Discovery and optimization of potent, selective, and in vivo efficacious BCATm inhibitors
Deng, Hongfeng
Zhou, Jingye
Sundersingh, Flora
Messer, Jeff
Somers, Don
Beljean, Arthur
Belyanskaya, Svetlana
Bingham, Ryan
Blazensky, Emily
Boursier, Eric
Chai, Jing
Carter, Paul
Chung, Chun-wa
Daugan, Alain
Ding, Yun
Humphries, Eric
Kollmann, Chris
Smith, Sarah
Dodic, Nerina
Ancellin, Nicolas
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2015, 250

← 1 2 3 4 5 →