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Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor.
Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor.
- Source :
-
Science advances [Sci Adv] 2019 May 22; Vol. 5 (5), pp. eaav3660. Date of Electronic Publication: 2019 May 22 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- Replication stress (RS) is a cancer hallmark; chemotherapeutic drugs targeting RS are widely used as treatments for various cancers. To develop next-generation RS-inducing anticancer drugs, cell division cycle 7 (CDC7) has recently attracted attention as a target. We have developed an oral CDC7-selective inhibitor, TAK-931, as a candidate clinical anticancer drug. TAK-931 induced S phase delay and RS. TAK-931-induced RS caused mitotic aberrations through centrosome dysregulation and chromosome missegregation, resulting in irreversible antiproliferative effects in cancer cells. TAK-931 exhibited significant antiproliferative activity in preclinical animal models. Furthermore, in indication-seeking studies using large-scale cell panel data, TAK-931 exhibited higher antiproliferative activities in RAS -mutant versus RAS -wild-type cells; this finding was confirmed in pancreatic patient-derived xenografts. Comparison analysis of cell panel data also demonstrated a unique efficacy spectrum for TAK-931 compared with currently used chemotherapeutic drugs. Our findings help to elucidate the molecular mechanisms for TAK-931 and identify potential target indications.
- Subjects :
- Animals
Cell Line, Tumor
Cell Proliferation
Cell Separation
Cell Survival
Centrosome drug effects
Chromosome Aberrations drug effects
Computational Biology
Drug Resistance, Neoplasm drug effects
Drug Screening Assays, Antitumor
Female
HeLa Cells
Humans
Inhibitory Concentration 50
Kaplan-Meier Estimate
Mice
Mice, Inbred BALB C
Mitosis drug effects
Models, Animal
Mutation
Neoplasm Transplantation
Pancreatic Neoplasms drug therapy
Protein Binding
Protein Kinase Inhibitors pharmacology
Proteomics
Treatment Outcome
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Cell Cycle Proteins antagonists & inhibitors
Protein Serine-Threonine Kinases antagonists & inhibitors
Pyrazolones pharmacology
Pyrimidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2375-2548
- Volume :
- 5
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Science advances
- Publication Type :
- Academic Journal
- Accession number :
- 31131319
- Full Text :
- https://doi.org/10.1126/sciadv.aav3660