scholarly journals Characterization of a new small-molecule inhibitor of HDAC6 in glioblastoma

2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Jaione Auzmendi-Iriarte ◽  
Ander Saenz-Antoñanzas ◽  
Idoia Mikelez-Alonso ◽  
Estefania Carrasco-Garcia ◽  
Maitena Tellaetxe-Abete ◽  
...  
Keyword(s):  
Small Molecule ◽  
Specific Inhibitor ◽  
Small Molecule Inhibitor ◽  
Cell Subpopulation ◽  
Histone Deacetylase 6 ◽  
Molecule Inhibitor ◽  
Reduce Tumor Growth ◽  
Hdac6 Inhibitor ◽  
High Cytotoxic Activity

Abstract Histone deacetylase 6 (HDAC6) is an epigenetic modifier that is an attractive pharmacological target in cancer. In this work, we show that HDAC6 is elevated in glioblastoma, the most malignant and common brain tumor in adults, in which its high levels correlate with poor patient survival and is more abundant in glioma stem cell subpopulation. Moreover, we identified a new small-molecule inhibitor of HDAC6, which presents strong sensitivity for HDAC6 inhibition and exerts high cytotoxic activity, alone or in combination with temozolomide. It is also able to significantly reduce tumor growth in vivo. Transcriptomic analysis of patient-derived glioma stem cells revealed an increase in cell differentiation and cell death pathways, as well as a decrease in cell-cycle activity and cell division by the treatment with the compound. Finally, the comparison with a pan-HDAC inhibitor, Vorinostat (SAHA), or HDAC6-specific inhibitor, Tubastatin A, showed higher target specificity and antitumor activity of the new HDAC6 inhibitor. In conclusion, our data reveal the efficacy of a novel HDAC6 inhibitor in glioblastoma preclinical setting.

scholarly journals A Novel Small-Molecule Inhibitor of Protein Kinase D Blocks Pancreatic Cancer Growth In vitro and In vivo

2010 ◽  
Vol 9 (5) ◽  
pp. 1136-1146 ◽  
Author(s):  
Kuzhuvelil B. Harikumar ◽  
Ajaikumar B. Kunnumakkara ◽  
Nobuo Ochi ◽  
Zhimin Tong ◽  
Amit Deorukhkar ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Protein Kinase ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Cancer Growth ◽  
Protein Kinase D ◽  
Molecule Inhibitor

A Novel Small Molecule Inhibitor for Aurora-A Kinase Inhibits the Growth of Cervical Cancer In Vitro and In Vivo.

2010 ◽  
Vol 83 (Suppl_1) ◽  
pp. 344-344
Author(s):  
Patricia Y. Akinfenwa ◽  
Nonna V. Kolomeyevskaya ◽  
Claire M. Mach ◽  
Zhen Li ◽  
Matthew L. Anderson
Keyword(s):  
Cervical Cancer ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Molecule Inhibitor

scholarly journals In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

2020 ◽  
Vol 73 (1) ◽  
pp. 147-161 ◽  
Author(s):  
Eliot J. Davidowitz ◽  
Pavan K. Krishnamurthy ◽  
Patricia Lopez ◽  
Heidy Jimenez ◽  
Leslie Adrien ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Self Association ◽  
In Vivo Validation

scholarly journals A Small Molecule Inhibitor of the β-Catenin-TCF4 Interaction Suppresses Colorectal Cancer Growth In Vitro and In Vivo

EBioMedicine ◽  
2017 ◽  
Vol 25 ◽  
pp. 22-31 ◽  
Author(s):  
Seung Ho Shin ◽  
Do Young Lim ◽  
Kanamata Reddy ◽  
Margarita Malakhova ◽  
Fangfang Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Cancer Growth ◽  
Molecule Inhibitor

Preclinical evaluation of SC0245, a small molecule inhibitor of ATR kinase.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15642-e15642
Author(s):  
Jian Wang ◽  
Qi Li ◽  
Yuanfeng Xia ◽  
Chi-Chung Chan ◽  
Xusheng Yuan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Mouse Models ◽  
Small Molecule ◽  
Kinase Inhibitor ◽  
Small Molecule Inhibitor ◽  
Inhibiting Activity ◽  
Molecule Inhibitor ◽  
Phosphoinositide 3 Kinase ◽  
Atr Kinase

e15642 Background: The ataxia telangiectasia and Rad3-related (ATR) kinase is a member of the phosphoinositide 3-kinase related kinase (PIKK) family. ATR plays an important role in maintaining genome integrity during DNA replication through the activation of Chk1, and regulation of the DNA damage response (DDR). Replication stress (RS) is a major source of genomic instability in cancer, and targeting the RS-response kinase ATR has emerged as a promising antitumor approach. The purpose of this study was to investigate the antitumor activity of SC0245, a small molecule inhibitor of ATR kinase, in preclinical models of ATM pathway or ARID1A deficient solid tumors. Methods: The kinase inhibiting activity of SC0245 was determined using the ATR/ATRIP(h) complex assays. The cellular anti-proliferative activity was evaluated with tumor cells which was ATM pathway or ARID1A deficient. The in vivo antitumor activity of SC0245 was evaluated in ATM pathway or ARID1A deficient cell-derived xenograft (CDX) mouse models of gastric cancer (SNU-601) and colorectal adenocarcinoma (LoVo). Results: SC0245 displayed potent kinase inhibiting activity for ATR/ATRIP complex with IC50 14 nM, and had outstanding selectivity in the 104 onco-kinase panels. SC0245 significantly inhibited cell proliferation in ATM pathway or ARID1A deficient LoVo cells with IC50 0.163 μM, SNU-601 cells with IC50 0.218 μM. SC0245 showed excellent pharmacokinetics (PK) features with oral bioavailability ( > 80%) in mouse, rat and dog. Moreover, in the SNU601 and LoVo CDX mouse models, SC0245 oral administration significantly inhibited tumor growth, with better efficacy than AZD6738. Conclusions: SC0245, a novel potent ATR kinase inhibitor, has marked antitumor efficacy in the ATM pathway or ARID1A deficient solid tumor animal models, and has outstanding PK properties. SC0245 represents a promising clinical candidate for treating solid cancers, such as gastric and colorectal cancers.

Sign in / Sign up

Export Citation Format

Share Document