2. Academic Validation
  3. Discovery of MTR-106 as a highly potent G-quadruplex stabilizer for treating BRCA-deficient cancers

Discovery of MTR-106 as a highly potent G-quadruplex stabilizer for treating BRCA-deficient cancers

  • Invest New Drugs. 2021 Oct;39(5):1213-1221. doi: 10.1007/s10637-021-01096-4.
Meng-Zhu Li  # 1 2,  Tao Meng  # 2 3,  Shan-Shan Song 1 2,  Xu-Bin Bao 1 2,  Lan-Ping Ma 2 3,  Ning Zhang 1 2,  Ting Yu 2 3,  Yong-Liang Zhang 2 3,  Bing Xiong 4 5,  Jing-Kang Shen 6 7,  Ze-Hong Miao 8 9,  Jin-Xue He 10 11
Affiliations

Affiliations

  • 1 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, No.19A Yuquan Road, 100049, Beijing, China.
  • 3 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 University of Chinese Academy of Sciences, No.19A Yuquan Road, 100049, Beijing, China. [email protected].
  • 5 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 6 University of Chinese Academy of Sciences, No.19A Yuquan Road, 100049, Beijing, China. [email protected].
  • 7 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 8 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 9 University of Chinese Academy of Sciences, No.19A Yuquan Road, 100049, Beijing, China. [email protected].
  • 10 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 11 University of Chinese Academy of Sciences, No.19A Yuquan Road, 100049, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 33710464 DOI: 10.1007/s10637-021-01096-4
Abstract

G-quadruplexes (G4s) are DNA or RNA structures formed by guanine-rich repeating sequences. Recently, G4s have become a highly attractive therapeutic target for BRCA-deficient cancers. Here, we show that a substituted Quinolone amide compound, MTR-106, stabilizes DNA G-quadruplexes in vitro. MTR-106 displayed significant antiproliferative activity in homologous recombination repair (HR)-deficient and PARP Inhibitor (PARPi)-resistant Cancer cells. Moreover, MTR-106 increased DNA damage and promoted cell cycle arrest and Apoptosis to inhibit cell growth. Importantly, its oral and i.v. administration significantly impaired tumor growth in BRCA-deficient xenograft mouse models. However, MTR-106 showed modest activity against talazoparib-resistant xenograft models. In rats, the drug rapidly distributes to tissues within 5 min, and its average concentrations were 12-fold higher in the tissues than in the plasma. Overall, we identified MTR-106 as a novel G-quadruplex stabilizer with high tissue distribution, and it may serve as a potential Anticancer agent.

Keywords

BRCA-deficiency; DNA damage; G-quadruplex stabilizer; MTR-106; PARP inhibitor.

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