2. Academic Validation
  3. Discovery of ART0380, a Potent and Selective ATR Kinase Inhibitor Undergoing Phase 2 Clinical Studies for the Treatment of Advanced or Metastatic Solid Cancers

Discovery of ART0380, a Potent and Selective ATR Kinase Inhibitor Undergoing Phase 2 Clinical Studies for the Treatment of Advanced or Metastatic Solid Cancers

  • J Med Chem. 2024 Dec 26;67(24):21890-21904. doi: 10.1021/acs.jmedchem.4c01595.
Christopher L Carroll 1,  Michael G Johnson 2,  Yanbing Ding 3,  Zhijun Kang 1,  R S K Vijayan 1,  Jennifer P Bardenhagen 1,  Cheng Fang 3,  David Lapointe 2,  Meng Li 3,  Chiu-Yi Liu 4,  Xiaobing Lv 3,  XiaoYan Ma 4,  Jihai Pang 1,  Hannah E Shepard 1,  Catalina Suarez 1,  Anne Ju Yau 1,  Christopher C Williams 1,  Qi Wu 1,  Robert A Heald 5,  Helen M R Robinson 5,  Graeme C M Smith 5,  Jason B Cross 1,  Mary K Geck Do 1,  Yongying Jiang 1,  Sarah Lively 2,  Timothy A Yap 1 6 7,  Virginia Giuliani 4,  Timothy Heffernan 4,  Philip Jones 1,  M Emilia Di Francesco 1
Affiliations

Affiliations

  • 1 Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
  • 2 ChemPartner Corporation, South San Francisco, California 94080, United States.
  • 3 ChemPartner Corporation, Shanghai 201203, China.
  • 4 Translational Research to AdvanCe Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
  • 5 Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge CB223FH, U.K.
  • 6 Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
  • 7 Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
PMID: 39630604 DOI: 10.1021/acs.jmedchem.4c01595
Abstract

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 (6), 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 (6) 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.

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