Discovery of ART0380, a Potent and Selective ATR Kinase Inhibitor Undergoing Phase 2 Clinical Studies for the Treatment of Advanced or Metastatic Solid Cancers
One of the hallmarks of cancer is high levels of DNA replication stress and defects in the DNA damage response (DDR) pathways, which are critical for maintaining genomic integrity. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of the DDR machinery and an attractive therapeutic target, with multiple ATR inhibitors holding significant promise in ongoing clinical studies. Herein, we describe the discovery and characterization of ART0380 (<b>6</b>), a potent and selective ATR inhibitor with a compelling in vitro and in vivo pharmacological profile currently undergoing Phase 2 clinical studies in patients with advanced or metastatic solid tumors as monotherapy and in combination with DNA-damaging agents (NCT04657068 and NCT05798611). ART0380 (<b>6</b>) has a favorable human PK profile suitable for both intermittent and continuous once-daily (QD) dosing, characterized by a dose-proportional increase in exposure and low variability.
Authors
- Maria Emilia Di Francesco (ORCID: https://orcid.org/0000-0002-5132-1643)
- Qi Wu (ORCID: https://orcid.org/0000-0001-9879-5056)
- Michael G. Johnson (ORCID: https://orcid.org/0000-0001-9213-0598)
- Helen M.R. Robinson (ORCID: https://orcid.org/0000-0003-0414-0740)
- Fang Cheng (ORCID: https://orcid.org/0000-0002-8260-9244)
- Catalina Suarez
- Yongying Jiang (ORCID: https://orcid.org/0000-0001-7774-0136)
- Jason B. Cross (ORCID: https://orcid.org/0000-0002-0919-2833)
- Chiu-Yi Liu
- David Lapointe (ORCID: https://orcid.org/0000-0002-9697-0399)
- Sarah Lively (ORCID: https://orcid.org/0009-0003-4898-6470)
- Virginia Giuliani (ORCID: https://orcid.org/0000-0002-2439-4986)
- Mary Geck (ORCID: https://orcid.org/0009-0000-2927-9402)
- Christopher L. Carroll (ORCID: https://orcid.org/0000-0002-7212-7268)
- Christopher C. Williams (ORCID: https://orcid.org/0000-0001-7503-0149)
- Yanbing Ding (ORCID: https://orcid.org/0000-0002-0689-2199)
- Hannah E. Shepard
- XiaoYan Ma
- Timothy P. Heffernan (ORCID: https://orcid.org/0000-0002-3166-8922)
- Philip Jones (ORCID: https://orcid.org/0000-0001-6149-8293)
- Timothy Anthony Yap (ORCID: https://orcid.org/0000-0002-2154-3309)
- Robert A. Heald (ORCID: https://orcid.org/0000-0003-3425-7130)
- Xiaobing Lv
- Graeme C.M. Smith (ORCID: https://orcid.org/0000-0001-8320-4057)
- Anne Yau (ORCID: https://orcid.org/0000-0002-1603-7428)
- Jennifer Bardenhagen (ORCID: https://orcid.org/0009-0003-2442-8327)
- Meng Li (ORCID: https://orcid.org/0000-0002-3735-4000)
- R. S. K. Vijayan (ORCID: https://orcid.org/0000-0003-4868-8214)
- Zhijun Kang (ORCID: https://orcid.org/0009-0003-4234-6659)
- Jihai Pang
Institutions
- Babraham Institute (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Institute of Cancer Research (CA)
- Center for Personalized Cancer Treatment (NL)
- Translational Research in Oncology (FR)
- dataPartner (Czechia) (CZ)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01595
- Citations
- 12
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 2.81