RT Journal Article
SR Electronic
T1 Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor
JF Science Advances
JO Sci Adv
FD American Association for the Advancement of Science
SP eaav3660
DO 10.1126/sciadv.aav3660
VO 5
IS 5
A1 Iwai, Kenichi
A1 Nambu, Tadahiro
A1 Dairiki, Ryo
A1 Ohori, Momoko
A1 Yu, Jie
A1 Burke, Kristine
A1 Gotou, Masamitsu
A1 Yamamoto, Yukiko
A1 Ebara, Shunsuke
A1 Shibata, Sachio
A1 Hibino, Ryosuke
A1 Nishizawa, Satoru
A1 Miyazaki, Tohru
A1 Homma, Misaki
A1 Oguro, Yuya
A1 Imada, Takashi
A1 Cho, Nobuo
A1 Uchiyama, Noriko
A1 Kogame, Akifumi
A1 Takeuchi, Toshiyuki
A1 Kurasawa, Osamu
A1 Yamanaka, Kazunori
A1 Niu, Huifeng
A1 Ohashi, Akihiro
YR 2019
UL http://advances.sciencemag.org/content/5/5/eaav3660.abstract
AB 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.