A Phase 1, Open-Label, Multiple-Ascending-Dose Study of DS-2248, an Orally Bioavailable Heat Shock Protein 90 Inhibitor, in Subjects With Advanced Solid Tumors

This phase 1 clinical trial is intended to understand the safety and tolerability of a new anticancer drug in subjects with advanced solid tumors. The patients who qualify for the study will receive a once daily dose of the drug taken by mouth and will undergo several tests to measure the drug in the blood and to understand the safety, tolerability and any effect of the drug on the tumor. The antitumor effect of the drug is not known in human.

开始日期2011-03-29

申办/合作机构

Daiichi Sankyo, Inc.

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100 项与 DS-2248 相关的临床结果

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100 项与 DS-2248 相关的转化医学

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100 项与 DS-2248 相关的专利（医药）

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项与 DS-2248 相关的文献（医药）

2021-06-01·Translational Cancer Research4区 · 医学

Effects of a combined treatment regimen consisting of Hsp90 inhibitor DS-2248 and radiation in vitro and in a tumor mouse model

4区 · 医学

Article

作者: Manabe, Yoshihiko ; Kondo, Takuhito ; Kawai, Tatsuya ; Shibamoto, Yuta ; Nakamura, Koichi ; Murai, Taro ; Matsuo, Masayuki ; Nakashima, Masahiro ; Sugie, Chikao ; Wang, Zhen

BACKGROUNDHeat shock protein 90 (HSP90) is a molecular chaperone that is responsible for the conformational maintenance of several client proteins that play important roles in DNA damage repair, apoptosis following radiation, and resistance to radiation therapy. DS-2248 (tricyclic pyrazolopyrimidine derivative) is a newly-developed, orally available inhibitor of HSP90 with low adverse effects. We investigated the combined effects of radiation and DS-2248 in vitro and in vivo.METHODSSCCVII squamous cell carcinoma cells and tumors transplanted in C3H/HeN mice were used. In vitro combined effects of X-ray radiation and DS-2248 were investigated using a colony assay. Phosphorylated histone H2AX (γH2AX) was quantified after 2-Gy irradiation with or without 24-hour pretreatment with DS-2248. The mice bearing SCCVII tumors received oral DS-2248 10 times over 2 weeks and received local irradiation with doses of 1, 2, 3, and 4 Gy delivered 6 times over 2 weeks. Then, tumor volumes were measured.RESULTSRadiation plus pretreatment with 50 nM DS-2248 for 24 hours produced synergistic effects on SCCVII cells. γH2AX foci persisted after radiation for longer periods (6 and 24 hours) in DS-2248-treated cells than in control cells. In vivo, the combined effects appeared to be additive when 5 or 10 mg/kg DS-2248 was combined with total radiation doses of 6-18 Gy, but the effect was considered supra-additive when 15 mg/kg of DS-2248 was combined with a total dose of 24 Gy.CONCLUSIONSThe combined effects of DS-2248 and radiation were additive at low drug and radiation doses, but may have been supra-additive at higher doses. Inhibition of slow repair of DNA double strand breaks (i.e., homologous recombination) was considered to contribute to this combined effect.

100 项与 DS-2248 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
晚期恶性实体瘤	临床1期	美国	Daiichi Sankyo UK Ltd.	2011-03-29
晚期恶性实体瘤	临床1期	美国	Daiichi Sankyo, Inc.	2011-03-29
非小细胞肺癌	临床1期	美国	Daiichi Sankyo UK Ltd.	2011-03-29
非小细胞肺癌	临床1期	美国	Daiichi Sankyo, Inc.	2011-03-29