TY  - JOUR
AU  - Chen, Xin
AU  - Wang, Jiayun
AU  - Zhao, Peng
AU  - Dang, Baiyun
AU  - Liang, Ting
AU  - Steimbach, Raphael
AU  - Miller, Aubry
AU  - Liu, Jia
AU  - Wang, Xin
AU  - Zhang, Tongtong
AU  - Luan, Xiaofa
AU  - Hu, Jiadong
AU  - Gao, Jinming
TI  - Tetrahydro-β-carboline derivatives as potent histone deacetylase 6 inhibitors with broad-spectrum antiproliferative activity.
JO  - European journal of medicinal chemistry
VL  - 260
SN  - 0009-4374
CY  - Amsterdam [u.a.]
PB  - Elsevier Science
M1  - DKFZ-2023-01807
SP  - 115776
PY  - 2023
AB  - A series of tetrahydro-β-carboline (THβC)-based hydroxamic acids were rationally designed and synthesized as novel selective HDAC6 inhibitors (sHDAC6is) by the application of scaffold hopping strategy. Several THβC analogues were highly potent (IC50 < 5 nM) and selective against HDAC6 enzyme and exhibited good antiproliferative activity against human multiple myeloma (MM) cell. Molecular docking interpreted the structure activity relationship (SAR). Target engagement of HDAC6 was confirmed in RPMI-8226 cells using the WB assay. In vitro, (1S, 3R)-1-(4-chlorophenyl)-N-(4-(hydroxycarbamoyl)benzyl)-2,3,4,9-tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxamide (14g) showed potent broad antiproliferative activity against various tumors including leukemia, colon cancer, melanoma, and breast cancer cell lines, better than ACY-1215. Moreover, 14g also showed good pharmacokinetics properties in mice via oral administration.
KW  - Antiproliferative (Other)
KW  - HDAC6 inhibitor (Other)
KW  - Selectivity (Other)
KW  - Synthesis (Other)
KW  - THβC (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37660484
DO  - DOI:10.1016/j.ejmech.2023.115776
UR  - https://inrepo02.dkfz.de/record/282518
ER  -