Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor

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-sele...

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Published in:Science advances 2019-05, Vol.5 (5), p.eaav3660-eaav3660
Main Authors: Iwai, Kenichi, Nambu, Tadahiro, Dairiki, Ryo, Ohori, Momoko, Yu, Jie, Burke, Kristine, Gotou, Masamitsu, Yamamoto, Yukiko, Ebara, Shunsuke, Shibata, Sachio, Hibino, Ryosuke, Nishizawa, Satoru, Miyazaki, Tohru, Homma, Misaki, Oguro, Yuya, Imada, Takashi, Cho, Nobuo, Uchiyama, Noriko, Kogame, Akifumi, Takeuchi, Toshiyuki, Kurasawa, Osamu, Yamanaka, Kazunori, Niu, Huifeng, Ohashi, Akihiro
Format: Article
Language:English
Subjects:
Cancer
Cell Biology
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Summary: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 -mutant versus -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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aav3660