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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.

Authors :
Iwai K
Nambu T
Dairiki R
Ohori M
Yu J
Burke K
Gotou M
Yamamoto Y
Ebara S
Shibata S
Hibino R
Nishizawa S
Miyazaki T
Homma M
Oguro Y
Imada T
Cho N
Uchiyama N
Kogame A
Takeuchi T
Kurasawa O
Yamanaka K
Niu H
Ohashi A
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.

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