Indolo[3,2-c]isoquinoline Hydroxamic Acid Derivatives as Novel Orally Topoisomerase-Histone Deacetylase Dual Inhibitors for NSCLC Therapy DOI

Bichuan Wang,

Ting Shi,

Shuolei Jia

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 23, 2024

Based on the synergistic effects of topoisomerase (Top) inhibitors and histone deacetylase (HDAC) in cancer therapy, a series novel Top/HDAC dual were designed synthesized herein. The optimal compound 31 was identified to simultaneously inhibit both Tops HDACs with potent antiproliferative activity against nonsmall cell lung (NSCLC). Mechanistic studies indicated that increasing reactive oxygen species levels damages DNA, inhibiting colony formation migration inducing apoptosis cycle arrest. Noteworthily, orally active NSCLC xenograft model, its antitumor efficacy (TGI = 77.5%, 100 mg/kg) superior HDAC inhibitor SAHA combination Top irinotecan. Consequently, this work highlights therapeutic potential as therapy provides valuable lead compounds for further development agents solid tumor therapy.

Language: Английский

Discovery of 5-Phenylthiazol-2-amine Derivatives as Novel PI4KIIIβ Inhibitors with Efficacious Antitumor Activity by Inhibiting the PI3K/AKT Axis DOI

Bichuan Wang,

Siyuan Hao, Fang Han

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

To develop novel PI4KIIIβ inhibitors and explore their antitumor activity, a series of 5-phenylthiazol-2-amine derivatives were synthesized by structural modifications PIK93. Biological assay results indicated that compounds 16 43 exhibited superior selective inhibitory antiproliferative activity than Mechanistic studies revealed the two inhibit PI3K/AKT pathway more effectively, thereby inducing cancer cell apoptosis, cycle arrest in G2/M phase autophagy. Importantly, vivo toxicity pharmacodynamics showed safety to commercially available axis inhibitor alpelisib, obviously small lung H446 xenograft models. Overall, this work highlights therapeutic potential treatment tumors, provides candidates viable drug development strategies for inhibitors.

Language: Английский

Citations

1
Synthesis, Structural Modification, and Antismall Cell Lung Cancer Activity of 3-Arylisoquinolines with Dual Inhibitory Activity on Topoisomerase I and II DOI

Xuemei Deng,

Yuying Wang, Xi Yang

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

To overcome the compensatory effect between Topo I and II, one of reasons accounting for resistance SCLC patients, we are pioneering use 3-arylisoquinolines to develop dual inhibitors I/II management SCLC. A total 46 new compounds were synthesized. Compounds 3g (IC50 = 1.30 μM NCI-H446 cells 1.42 NCI-H1048 cells) 3x 1.32 2.45 selected detailed pharmacological investigation, due their outstanding cytotoxicity II inhibitory activity. effectively prevent cell proliferation, invasion, migration in vitro, byinducing mitochondrial apoptosis inhibiting PI3K/Akt/mTOR pathway. Their vivo tumor inhibition rate is comparable etoposide with lower toxicity. These results indicated potential therapeutic values as treating

Language: Английский

Citations

0
Indolo[3,2-c]isoquinoline Hydroxamic Acid Derivatives as Novel Orally Topoisomerase-Histone Deacetylase Dual Inhibitors for NSCLC Therapy DOI

Bichuan Wang,

Ting Shi,

Shuolei Jia

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 23, 2024

Based on the synergistic effects of topoisomerase (Top) inhibitors and histone deacetylase (HDAC) in cancer therapy, a series novel Top/HDAC dual were designed synthesized herein. The optimal compound 31 was identified to simultaneously inhibit both Tops HDACs with potent antiproliferative activity against nonsmall cell lung (NSCLC). Mechanistic studies indicated that increasing reactive oxygen species levels damages DNA, inhibiting colony formation migration inducing apoptosis cycle arrest. Noteworthily, orally active NSCLC xenograft model, its antitumor efficacy (TGI = 77.5%, 100 mg/kg) superior HDAC inhibitor SAHA combination Top irinotecan. Consequently, this work highlights therapeutic potential as therapy provides valuable lead compounds for further development agents solid tumor therapy.

Language: Английский

Citations

0