2. Academic Validation
  3. Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator

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

  • J Med Chem. 2024 Apr 11;67(7):5259-5271. doi: 10.1021/acs.jmedchem.3c02384.
Christopher G Thomson 1,  Thomas D Aicher 2,  Weiwei Cheng 3,  Hongwen Du 3,  Crissy Dudgeon 4,  An-Hu Li 4,  Baozhong Li 3,  Eric Lightcap 4,  Diheng Luo 5,  Mark Mulvihill 4,  Pengwei Pan 3,  Benjamin F Rahemtulla 1,  Alan C Rigby 4,  Bradley Sherborne 1,  Sanjeev Sood 6,  David Surguladze 4,  Eric P A Talbot 1,  Feven Tameire 4,  Simon Taylor 1,  Yi Wang 3,  Paulina Wojnarowicz 4,  Fenfen Xiao 5,  Savithri Ramurthy 4
Affiliations

Affiliations

  • 1 Integrated Drug Discovery Services, Pharmaron UK Ltd., West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, U.K.
  • 2 Department of Chemistry, Lycera Corporation, Ann Arbor, Michigan 48103, United States.
  • 3 Pharmaron Beijing, Company Ltd., No. 6, TaiHe Road, BDA, Beijing 100176, China.
  • 4 HiberCell Inc., 619 West 54th Street, New York, New York 10019, United States.
  • 5 Pharmaron Xi'an, Company Ltd., No. 1, 12th Fengcheng Road, Xi'an 710018, China.
  • 6 Preformulation and Preclinical Services, Pharmaron UK Ltd., West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, U.K.
PMID: 38530741 DOI: 10.1021/acs.jmedchem.3c02384
Abstract

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.

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