Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy

Acta Pharmaceutica Sinica B

Yuan He¹  Meng Xin²  Congcong Xu³  Chunlin Zhuang³  Jing Zhu³  Wannian Zhang³  Zhibin Wang⁴ 

[1] Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai 200071, China;School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China;School of Pharmacy, Second Military Medical University, Shanghai 200433, China;Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China;

关键词: Necroptosis;    RIP1;    RIP3;    Selectivity;    Ulcerative colitis;   

DOI  :  

来源: DOAJ

【 摘 要 】

Receptor-interacting protein (RIP) kinase 1 is involved in immune-mediated inflammatory diseases including ulcerative colitis (UC) by regulating necroptosis and inflammation. Our group previously identified TAK-632 (5) as an effective necroptosis inhibitor by dual-targeting RIP1 and RIP3. In this study, using ligand-based substituent-anchoring design strategy, we focused on the benzothiazole ring to obtain a series of TAK-632 analogues showing significantly improving on the anti-necroptosis activity and RIP1 selectivity over RIP3. Among them, a conformational constrained fluorine-substituted derivative (25) exhibited 333-fold selectivity for RIP1 (Kd = 15 nmol/L) than RIP3 (Kd > 5000 nmol/L). This compound showed highly potent activity against cell necroptosis (EC50 = 8 nmol/L) and systemic inflammatory response syndrome (SIRS) induced by TNF-α in vivo. Especially, it was able to exhibit remarkable anti-inflammatory treatment efficacy in a DSS-induced mouse model of UC. Taken together, the highly potent, selective, orally active anti-necroptosis inhibitor represents promising candidate for clinical treatment of UC.

【 授权许可】

Unknown