AbstractBackgroundRifaquizinone (RFQ, TNP-2092) is a novel multitargeting drug conjugate in development for the treatment of prosthetic joint infections (PJIs). RFQ exerts its antibacterial activity by inhibiting RNA polymerase, DNA gyrase, and topoisomerase IV. This study sought to investigate the safety/tolerability of RFQ following intra-articular (IA) administration in Beagle dogs.MethodsForty Beagle dogs (20/sex) were randomly assigned to 4 groups (5/sex/group) to receive 0, 1, 2.5, and 5 mg/kg/day RFQ in 5% (w/v) glucose once daily for 14 days by IA administration into the right knee joint. All the dogs had a 14-day recovery period to assess the reversibility, persistence, or delayed occurrence of adverse effects. Blood and synovial fluid samples were collected and concentrations of RFQ in each matrix were determined by liquid chromatography tandem mass spectrometry.ResultsNo test article-related adverse effects in body weight, food consumption, temperature, clinical pathology, or organ weight were observed in any of the study groups. In 2.5 and 5 mg/kg/day groups, lameness, swelling and ulceration of right knee joint during treatment were observed. The 5 mg/kg group dosing was terminated prematurely due to marked arthritis on right knee joint. The no observed adverse effect level (NOAEL) was 1 mg/kg/day. At this dose level the steady state of RFQ concentrations in synovial fluid was achieved in 4 days and maintained until Day 14 (Figure 1). The mean RFQ concentrations on Day 14 in synovial fluids for male and female dogs were 35,900 and 19,200 ng/mL, respectively, as compared to the plasma Cmax 411 and 303 ng/mL for male and female dogs, respectively. Plasma toxicokinetics (TK) analysis indicated no apparent sex differences in systemic exposure at any dose level.ConclusionThe NOAEL of RFQ in dogs was 1 mg/kg/day via IA administration. The synovial fluid concentration at this dose level exceeded minimum biofilm bactericidal concentration inhibit 90% bacterial growth (MBBC90) levels for both S. aures and S. epidermidis. IA administration of RFQ is a promising option for the treatment of PJIs.DisclosuresHuan Wang, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee Qin Cheng, Master, TenNor Therapeutics (Suzhou) Ltd: Employee Weijian Ke, Master, TenNor Therapeutics (Suzhou) Ltd: Investigator Zhenkun Ma, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee

01 Nov 2024·Annals of the Rheumatic Diseases

Altered CD8+ T cell subpopulation in the bone marrow microenvironment of cynomolgus monkeys with spontaneous ankylosing spondylitis

Letter

Author: Chen, Siyu ; Bian, Zhenhua ; Luo, Panyue ; Jia, Huanhuan ; Zhao, Zhibin ; Guan, Yezhi ; Guan, Tangming ; He, Yi ; Liang, Shi ; Tang, Shuangjie ; Yuan, Junru ; Ye, Xiaolan ; Qiu, Jianming ; Liu, Jianxin ; Cai, Nvlue ; Yang, Wei ; Gao, Hongbin ; Li, Yongfeng ; Wan, Hongping ; Li, Wende

24 Aug 2023·Journal of Medicinal Chemistry

Discovery, SAR Study of GST Inhibitors from a Novel Quinazolin-4(1H)-one Focused DNA-Encoded Library

Article

Author: Li, Kaige ; Zhu, Jian ; Zhang, Xu ; Song, Weixiao ; Mu, Baiyang ; Jin, Rui ; Zhang, Minmin ; Lu, Weiwei ; Shen, Aijun ; Meng, Linghua ; Hu, Hangchen ; Wang, Xingyu ; Hong, Yu ; Suo, Yanrui ; Wen, Xin ; Duan, Zhiqiang ; Lu, Xiaojie

The DNA-encoded library (DEL) is a powerful hit-generation tool in drug discovery. This study describes a new DEL with a privileged scaffold quinazolin-4(3H)-one developed by a robust DNA-compatible multicomponent reaction and a series of novel glutathione S-transferase (GST) inhibitors that were identified through affinity-mediated DEL selection. A novel inhibitor 16 was subsequently verified with an inhibitory potency value of 1.55 ± 0.02 μM against SjGST and 2.02 ± 0.20 μM against hGSTM2. Further optimization was carried out via various structure-activity relationship studies. And especially, the co-crystal structure of the compound 16 with the SjGST was unveiled, which clearly demonstrated its binding mode was quite different from the known GSH-like compounds. This new type of probe is likely to play a different role compared with the GSH, which may provide new opportunities to discover more potent GST inhibitors.

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