Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator

被引：4

作者：

Thomson, Christopher G. ^{[1
]}

Aicher, Thomas D. ^{[2
,3
]}

Cheng, Weiwei ^{[4
]}

Du, Hongwen ^{[4
]}

Dudgeon, Crissy ^{[5
]}

Li, An-Hu ^{[5
]}

Li, Baozhong ^{[4
]}

Lightcap, Eric ^{[5
]}

Luo, Diheng ^{[6
]}

Mulvihill, Mark ^{[5
]}

Pan, Pengwei ^{[4
]}

Rahemtulla, Benjamin F. ^{[1
]}

Rigby, Alan C. ^{[5
]}

Sherborne, Bradley ^{[1
]}

Sood, Sanjeev ^{[7
]}

Surguladze, David ^{[5
]}

Talbot, Eric P. A. ^{[1
]}

Tameire, Feven ^{[5
]}

Taylor, Simon ^{[1
]}

Wang, Yi ^{[4
]}

Wojnarowicz, Paulina ^{[5
]}

Xiao, Fenfen ^{[6
]}

Ramurthy, Savithri ^{[5
]}

机构：

[1] Pharmaron UK Ltd, Integrated Drug Discovery Serv, Hoddesdon EN11 9FH, Herts, England

[2] Lycera Corp, Dept Chem, Ann Arbor, MI 48103 USA

[3] 13230 Campanile Court, Venice 34293, Florida, Uruguay

[4] Pharmaron Beijing Co Ltd, Beijing 100176, Peoples R China

[5] HiberCell Inc, New York, NY 10019 USA

[6] Pharmaron Xian Co Ltd, Xian 710018, Peoples R China

[7] Pharmaron UK Ltd, Preformulat & Preclin Serv, Hoddesdon EN11 9FH, Herts, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 07期

关键词：

STRESS RESPONSES; CELL-SURVIVAL; PROTEIN; IDENTIFICATION; RESISTANCE; PATHWAY;

D O I：

10.1021/acs.jmedchem.3c02384

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of activators of GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition.

引用

页码：5259 / 5271

页数：13

共 34 条

[1]

[Anonymous], ALL KINOMESCAN KIN S

[2] Knocking out the door to tunicamycin entry [J].

Bassik, Michael C. ;

Kampmann, Martin .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (29) :11731-11732

[3] Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors [J].

Calvo, Veronica ;

Surguladze, David ;

Li, An-Hu ;

Surman, Matthew D. ;

Malibhatla, Srikanth ;

Bandaru, Madhavarao ;

Jonnalagadda, Suresh Krishna ;

Adarasandi, Ravi ;

Velmala, Madhusudhan ;

Singireddi, Durga Rama Prasad ;

Velpuri, Mahendar ;

Nareddy, Bhaskar Reddy ;

Sastry, Visweswara ;

Mandati, Chiranjeevi ;

Guguloth, Rambabu ;

Siddiqui, Shapi ;

Patil, Basanagoud S. ;

Chad, Elena ;

Wolfley, Jennifer ;

Gasparek, Jennifer ;

Feldman, Kirsten ;

Betzenhauser, Matthew ;

Wiens, Brent ;

Koszelak-Rosenblum, Mary ;

Zhu, Guangyu ;

Du, Hongwen ;

Rigby, Alan C. ;

Mulvihill, Mark J. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2021, 43

[4] Activation of Gcn2 by small molecules designed to be inhibitors [J].

Carlson, Kenneth R. ;

Georgiadis, Millie M. ;

Tameire, Feven ;

Staschke, Kirk A. ;

Wek, Ronald C. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2023, 299 (04)

[5] The Critical Role of Passive Permeability in Designing Successful Drugs [J].

Di, Li ;

Artursson, Per ;

Avdeef, Alex ;

Benet, Leslie Z. ;

Houston, J. Brian ;

Kansy, Manfred ;

Kerns, Edward H. ;

Lennernaes, Hans ;

Smith, Dennis A. ;

Sugano, Kiyohiko .

CHEMMEDCHEM, 2020, 15 (20) :1862-1874

[6] Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-Binding domain [J].

Dong, JS ;

Qiu, HF ;

Garcia-Barrio, M ;

Anderson, J ;

Hinnebusch, AG .

MOLECULAR CELL, 2000, 6 (02) :269-279

[7] Identification of Novel, Potent, and Orally Available GCN2 Inhibitors with Type I Half Binding Mode [J].

Fujimoto, Jun ;

Kurasawa, Osamu ;

Takagi, Terufumi ;

Liu, Xin ;

Banno, Hiroshi ;

Kojima, Takuto ;

Asano, Yasutomi ;

Nakamura, Akito ;

Nambu, Tadahiro ;

Hata, Akito ;

Ishii, Tsuyoshi ;

Sameshima, Tomoya ;

Debori, Yasuyuki ;

Miyamoto, Maki ;

Klein, Michael G. ;

Tjhen, Richard ;

Sang, Bi-Ching ;

Levin, Irena ;

Lane, Scott Weston ;

Snell, Gyorgy P. ;

Li, Ke ;

Kefala, Georgia ;

Hoffman, Isaac D. ;

Ding, Steve C. ;

Cary, Douglas R. ;

Mizojiri, Ryo .

ACS MEDICINAL CHEMISTRY LETTERS, 2019, 10 (10) :1498-1503

[8] ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death [J].

Han, Jaeseok ;

Backa, Sung Hoon ;

Hur, Junguk ;

Lin, Yu-Hsuan ;

Gildersleeve, Robert ;

Shan, Jixiu ;

Yuan, Celvie L. ;

Krokowski, Dawid ;

Wang, Shiyu ;

Hatzoglou, Maria ;

Kilberg, Michael S. ;

Sartor, Maureen A. ;

Kaufman, Randal J. .

NATURE CELL BIOLOGY, 2013, 15 (05) :481-+

[9] Perk is essential for translational regulation and cell survival during the unfolded protein response [J].

Harding, HP ;

Zhang, YH ;

Bertolotti, A ;

Zeng, HQ ;

Ron, D .

MOLECULAR CELL, 2000, 5 (05) :897-904

[10] An integrated stress response regulates amino acid metabolism and resistance to oxidative stress [J].

Harding, HP ;

Zhang, YH ;

Zeng, HQ ;

Novoa, I ;

Lu, PD ;

Calfon, M ;

Sadri, N ;

Yun, C ;

Popko, B ;

Paules, R ;

Stojdl, DF ;

Bell, JC ;

Hettmann, T ;

Leiden, JM ;

Ron, D .

MOLECULAR CELL, 2003, 11 (03) :619-633

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