2. Academic Validation
  3. Exploring the structural-activity relationship of hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine derivatives as potent and orally-bioavailable PARP7 inhibitors

Exploring the structural-activity relationship of hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine derivatives as potent and orally-bioavailable PARP7 inhibitors

  • Eur J Med Chem. 2023 Dec 5:261:115836. doi: 10.1016/j.ejmech.2023.115836.
Silong Zhang 1,  Yu Zhang 2,  Ziwei Wang 2,  Luolong Qing 2,  Shaojuan Fu 3,  Juan Xu 4,  Yuanyuan Li 5,  Huaxiang Fang 6,  Huan He 7
Affiliations

Affiliations

  • 1 Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China; College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, PR China; Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan, 430200, PR China.
  • 2 Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China; College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, PR China.
  • 3 Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China.
  • 4 College of Chemistry and Chemical Engineering, Hubei Polytechnic University, Huangshi, 435003, PR China; Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan, 430200, PR China.
  • 5 Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan, 430200, PR China; School of Life Science and Technology, Wuhan Polytechnic University, Wuhan, 430023, PR China. Electronic address: [email protected].
  • 6 Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan, 430200, PR China. Electronic address: [email protected].
  • 7 Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China; College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, PR China; Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan, 430200, PR China. Electronic address: [email protected].
PMID: 37826932 DOI: 10.1016/j.ejmech.2023.115836
Abstract

PARP7 has emerged as a promising anti-tumor target due to its crucial roles in nucleic acid sensing and immune regulation. Herein, we explored the structural-activity relationship of tricyclic PARP7 inhibitors containing a hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine motif. The effects of the chirality of the fused rings, the group conjugated to the fused rings, and the size of the linker on PARP7 inhibition were fully investigated. Our work leads to the discovery of an extremely potent and orally-bioavailable PARP7 Inhibitor, namely 18 (PARP7 inhibition IC50 = 0.56 nM), for efficacious treatment of lung Cancer in vivo. Notably, 18 showed acceptable bioavailability in ICR mice (F = 33.9%) and Beagle dogs (F = 45.2%). Further investigation of ADME-T properties suggested that 18 has the potential to be developed as a candidate drug molecule for PARP7-sensitive tumors.

Keywords

ADME-T; Cyclization; PARP7; Pharmacokinetic; Structural-activity relationship.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-155351
    PARP7 Inhibitor