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

This study highlights the successful collaboration between Pharmaron and HiberCell, which led to the discovery of HC-7366, a GCN2 kinase activator (General Control Nonderepressible 2) currently undergoing clinical investigation. Pharmaron’s integrated drug discovery service team played a pivotal role in this project, providing project leadership, scientific expertise, consultancy, and services in medicinal chemistry, DMPK, and CADD.

The paper outlines the rationale and preclinical drug discovery efforts that culminated in HC-7366, from early ADME goals and strategies to encouraging in vitro pharmacology and early xenograft studies for the candidate compound.

Pharmaron’s integrated drug discovery services enabled rapid responses to emerging scientific challenges and ensured seamless progression across disciplines and experiments. This efficient approach allowed the program to advance from lead identification to GMP batch production in just over a year.

Key Contributions by Pharmaron in the Discovery of HC-7366

  • Project Leadership: Guided the program from lead identification to GMP batch production in just over a year.
  • Medicinal Chemistry: Designed and synthesized a series of GCN2 kinase activators, balancing potency, selectivity, and ADME properties to enable clinical progression.
  • DMPK (Drug Metabolism and Pharmacokinetics): Delivered critical ADME insights, improving compound permeability, bioavailability, and in vivo exposure for robust preclinical evaluation and to line up the translation from preclinical exposure to human dose prediction.
  • CADD (Computer-Aided Drug Design): Applied computational modeling for ChemInformatics and  Structure-Based Design to build SAR understanding and compound design, accelerating the discovery of HC-7366.
  • Scientific Consultancy: Provided expert guidance to digest data, address emerging challenges, and ensure seamless progression across disciplines

Journal of Medicinal Chemistry 2024 Apr 11;67(7):5259-5271.

DOI: 10.1021/acs.jmedchem.3c02384

Access the publication at https://pubmed.ncbi.nlm.nih.gov/38530741/