Abstract:
:STAT3 has been validated as an attractive anticancer target due to its important roles in cancer initiation and progression. However, discovery of potent and selective STAT3 small-molecule inhibitors with druglike properties is still challenging. In this study, two series of substituted 2-phenylquinolines and 2-arylimidazo[1,2-a]pyridines were designed through structure-based drug discovery approach by condensing the privileged structures of STX-119 and SH4-54. Our study has resulted in the discovery of a number of highly potent and selective STAT3 inhibitors, exemplified by compound 39 with the privileged structure of 2-phenylimidazo[1,2-a]pyridine, which selectively inhibits phosphorylation of STAT3 and suppresses subsequent signaling pathway. Moreover, 39 inhibits cell growth, migration and invasion of human triple negative breast cancer (TNBC) cells lines. Consistently, it achieves significant and dose-dependent tumor growth inhibition in both cell line-derived and patient-derived xenograft tumor models in mice. These results clearly indicate that 39 is a highly potent and selective STAT3 inhibitor.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Huang Q,Zhong Y,Li B,Ouyang S,Deng L,Mo J,Shi S,Lv N,Wu R,Liu P,Hu W,Zhang X,Wang Ydoi
10.1016/j.ejmech.2021.113525keywords:
["Privileged structures","STAT3","Small-molecule inhibitors","Structure-based drug discovery"]subject
Has Abstractpub_date
2021-10-05 00:00:00pages
113525eissn
0223-5234issn
1768-3254pii
S0223-5234(21)00374-3journal_volume
221pub_type
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