TY - JOUR
T1 - Design, synthesis and evaluation of a pyrazolo[3,4-d]pyrimidine derivative as a novel and potent TGFβ1R1 inhibitor
AU - Wang, Yubo
AU - Liu, Yulin
AU - Zhang, Yan
AU - Zhang, Zixuan
AU - Xu, Lei
AU - Wang, Jiefu
AU - Yang, Yijie
AU - Hu, Biyu
AU - Yao, Yuhong
AU - Wei, Mingming
AU - Wang, Junfeng
AU - Tang, Bencan
AU - Zhang, Kun
AU - Liu, Shuangwei
AU - Yang, Guang
N1 - Publisher Copyright:
© 2024 Elsevier Masson SAS
PY - 2024/5/5
Y1 - 2024/5/5
N2 - The transforming growth factor β1 (TGFβ1)/SMAD signaling pathway regulates many vital physiological processes. The development of potent inhibitors targeting activin receptor-like kinase 5 (ALK5) would provide potential treatment reagents for various diseases. A significant number of ALK5 inhibitors have been discovered, and they are currently undergoing clinical evaluation at various stages. However, the clinical demands were far from being met. In this study, we utilized an alternative conformation-similarity-based virtual screening (CSVS) combined with a fragment-based drug designing (FBDD) strategy to efficiently discover a potent and active hit with a novel chemical scaffold. After structural optimization in the principle of group replacement, compound 57 was identified as the most promising ALK5 inhibitor. Compound 57 demonstrated significant inhibitory effects against the TGF-β1/SMAD signaling pathway. It could markedly attenuate the production of extracellular matrix (ECM) and deposition of collagen. Also, the lead compound showed adequate pharmacokinetic (PK) properties and good in vivo tolerance. Moreover, treatment with compound 57 in two different xerograph models showed significant inhibitory effects on the growth of pancreatic cancer cells. These results suggested that lead compound 57 refers as a promising ALK5 inhibitor both in vitro and in vivo, which merits further validation.
AB - The transforming growth factor β1 (TGFβ1)/SMAD signaling pathway regulates many vital physiological processes. The development of potent inhibitors targeting activin receptor-like kinase 5 (ALK5) would provide potential treatment reagents for various diseases. A significant number of ALK5 inhibitors have been discovered, and they are currently undergoing clinical evaluation at various stages. However, the clinical demands were far from being met. In this study, we utilized an alternative conformation-similarity-based virtual screening (CSVS) combined with a fragment-based drug designing (FBDD) strategy to efficiently discover a potent and active hit with a novel chemical scaffold. After structural optimization in the principle of group replacement, compound 57 was identified as the most promising ALK5 inhibitor. Compound 57 demonstrated significant inhibitory effects against the TGF-β1/SMAD signaling pathway. It could markedly attenuate the production of extracellular matrix (ECM) and deposition of collagen. Also, the lead compound showed adequate pharmacokinetic (PK) properties and good in vivo tolerance. Moreover, treatment with compound 57 in two different xerograph models showed significant inhibitory effects on the growth of pancreatic cancer cells. These results suggested that lead compound 57 refers as a promising ALK5 inhibitor both in vitro and in vivo, which merits further validation.
KW - Activin receptor-like kinase 5 inhibitor
KW - Conformation-similarity-based virtual screening
KW - Fragment-based drug design
KW - Pancreatic cancer
KW - SAR study
KW - TGFβ1/SMAD signaling pathway
UR - http://www.scopus.com/inward/record.url?scp=85190277717&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2024.116395
DO - 10.1016/j.ejmech.2024.116395
M3 - Article
C2 - 38626523
AN - SCOPUS:85190277717
SN - 0223-5234
VL - 271
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 116395
ER -