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TACH101, a first-in-class pan-inhibitor of KDM4 histone demethylase
被引:11
|作者:
Chandhasin, Chandtip
[1
]
Dang, Van
[1
]
Perabo, Frank
[1
]
Del Rosario, Joselyn
[2
]
Chen, Young K.
[2
]
Filvaroff, Ellen
[2
]
Stafford, Jeffrey A.
[3
]
Clarke, Michael
[4
]
机构:
[1] Tachyon Therapeut Inc, 1160 Battery St East Suite 100, San Francisco, CA 94111 USA
[2] Bristol Myers Squibbm, New York, NY USA
[3] 858 Therapeut, San Diego, CA USA
[4] Stanford Univ, Stanford, CA USA
关键词:
epigenetic;
histone lysine demethylase;
KDM4;
TACH101;
EMBRYONIC STEM;
CELL-PROLIFERATION;
ANDROGEN RECEPTOR;
SELF-RENEWAL;
JMJD2B;
EXPRESSION;
GASC1;
GENE;
HETEROCHROMATIN;
METHYLATION;
D O I:
10.1097/CAD.0000000000001514
中图分类号:
R73 [肿瘤学];
学科分类号:
100214 ;
摘要:
Histone lysine demethylase 4 (KDM4) is an epigenetic regulator that facilitates the transition between transcriptionally silent and active chromatin states by catalyzing the removal of methyl groups on histones H3K9, H3K36, and H1.4K26. KDM4 overamplification or dysregulation has been reported in various cancers and has been shown to drive key processes linked to tumorigenesis, such as replicative immortality, evasion of apoptosis, metastasis, DNA repair deficiency, and genomic instability. KDM4 also plays a role in epigenetic regulation of cancer stem cell renewal and has been linked to more aggressive disease and poorer clinical outcomes. The KDM4 family is composed of four main isoforms (KDM4A-D) that demonstrate functional redundancy and cross-activity; thus, selective inhibition of one isoform appears to be ineffective and pan-inhibition targeting multiple KDM4 isoforms is required. Here, we describe TACH101, a novel, small-molecule pan-inhibitor of KDM4 that selectively targets KDM4A-D with no effect on other KDM families. TACH101 demonstrated potent antiproliferative activity in cancer cell lines and organoid models derived from various histologies, including colorectal, esophageal, gastric, breast, pancreatic, and hematological malignancies. In vivo, potent inhibition of KDM4 led to efficient tumor growth inhibition and regression in several xenograft models. A reduction in the population of tumor-initiating cells was observed following TACH101 treatment. Overall, these observations demonstrate the broad applicability of TACH101 as a potential anticancer agent and support its advancement into clinical trials.
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页码:1122 / 1131
页数:10
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