title: Discovery of DS-5272 as a promising candidate: A potent and orally active p53-MDM2 interaction inhibitor.
abstract: We have published p53-MDM2 interaction inhibitors possessing a novel dihydroimidazothiazole scaffold. Although our lead compound 1 showed strong antitumor activity with single oral administration on a xenograft model using MV4-11 cells harboring wild-type p53, it needed a higher dose (200mg/kg) for distinct efficacy. We executed further optimization with the aim of improvement of potency and physicochemical properties. Thus optimal compounds were furnished by introducing fluorine moieties onto the phenyl ring at the C-6 position and the pyrrolidine part at the C-2 substituent; and modifying the terminal piperazine to 4,7-diazaspiro[2,5]octane variants. Furthermore, replacing 4-chlorophenyl on the C-5 position with pyridyl variant decreased nonspecific cytotoxicity significantly. Our exploration afforded DS-5272 indicating excellent antitumor efficacy from a dose of 25mg/kg on SJSA-1 xenografted models with high safety and good PK profiles, which has appropriate potency as a clinical candidate.
authors.affiliation: Medicinal Chemistry Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: miyazaki.masaki.p3@daiichisankyo.co.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyazaki
authors.affiliation: Medicinal Chemistry Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Uoto
authors.affiliation: Medicinal Chemistry Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Sugimoto
authors.affiliation: Medicinal Chemistry Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Naito
authors.affiliation: Medicinal Chemistry Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Medicinal Chemistry Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tooru
authors.initials: T
authors.lastname: Okayama
authors.affiliation: Medicinal Chemistry Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Haruko
authors.initials: H
authors.lastname: Kawato
authors.affiliation: Oncology Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Miyazaki
authors.affiliation: Oncology Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kitagawa
authors.affiliation: Oncology Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Seki
authors.affiliation: Oncology Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Setsuko
authors.initials: S
authors.lastname: Fukutake
authors.affiliation: Oncology Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Aonuma
authors.affiliation: Medicinal Chemistry Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tsunehiko
authors.initials: T
authors.lastname: Soga
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D005461:Fluorine / Q000737:chemistry; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000604310:DS-5272; D007093:Imidazoles; D011759:Pyrrolidines; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D005461:Fluorine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Dihydroimidazothiazole; MDM2; Protein–protein interaction inhibitor; p53