This is a Phase I dose escalation study of TCD-717, a novel drug that is a specific inhibitor of the enzyme choline kinase alpha, in patients with advanced solid tumors. The objectives of this study are to evaluate the safety of the drug and to determine the maximum tolerated dose and appropriate dose for phase II studies. Secondary objectives are to measure the efficacy of TCD-717; and in a substudy to be conducted in the MTD confirmation cohort only, to evaluate the potential correlation between the levels of tumor choline and tumor response to the choline kinase alpha inhibitor, TCD-717, using magnetic resonance spectroscopy. Pharmacokinetics analysis will be performed on patients enrolled in the maximum tolerated dose confirmation cohort.

开始日期2011-01-01

申办/合作机构

Traslational Cancer Drugs Pharma SL

100 项与 TCD-717 相关的临床结果

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100 项与 TCD-717 相关的转化医学

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100 项与 TCD-717 相关的专利（医药）

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项与 TCD-717 相关的文献（医药）

2018-02-27·Biochemistry3区 · 生物学

Identification of a Unique Inhibitor-Binding Site on Choline Kinase α

3区 · 生物学

Article

作者: Kall, Stefanie L. ; Lavie, Arnon ; Delikatny, Edward J.

Choline kinase α (ChoKα) is an enzyme that is upregulated in many types of cancer and has been shown to be tumorigenic. As such, it makes a promising target for inhibiting tumor growth. Though there have been several inhibitors synthesized for ChoKα, not all of them demonstrate the same efficacy in vivo, though the reasons behind this difference in potency are not clear. One particular inhibitor, designated TCD-717, has recently completed phase I clinical trials. Cell culture and in vitro studies support the powerful inhibitory effect TCD-717 has on ChoKα, but an examination of the inhibitor's interaction with the ChoKα enzyme has been missing prior to this work. Here we detail the 2.35 Å structure of ChoKα in complex with TCD-717. Examination of this structure in conjunction with kinetic assays reveals that TCD-717 does not bind directly in the choline pocket as do previously characterized ChoKα inhibitors, but rather in a proximal but novel location near the surface of the enzyme. The unique binding site identified for TCD-717 lends insight for the future design of more potent in vivo inhibitors for ChoKα.

PLoS ONE3区 · 综合性期刊

Combined 5-FU and ChoKα Inhibitors as a New Alternative Therapy of Colorectal Cancer: Evidence in Human Tumor-Derived Cell Lines and Mouse Xenografts

3区 · 综合性期刊

ArticleOA

作者: Juan Carlos Lacal ; Arancha Cebrián ; Teresa Gómez del Pulgar ; Maria Angeles Ramos ; Ana de la Cueva ; Ana Ramírez de Molina ; Nestor Álvarez-Ayerza

BACKGROUNDColorectal cancer (CRC) is the third major cause of cancer related deaths in the world. 5-fluorouracil (5-FU) is widely used for the treatment of colorectal cancer but as a single-agent renders low response rates. Choline kinase alpha (ChoKα), an enzyme that plays a role in cell proliferation and transformation, has been reported overexpressed in many different tumors, including colorectal tumors. ChoKα inhibitors have recently entered clinical trials as a novel antitumor strategy.METHODOLOGY/PRINCIPAL FINDINGSChoKα specific inhibitors, MN58b and TCD-717, have demonstrated a potent antitumoral activity both in vitro and in vivo against several tumor-derived cell line xenografts including CRC-derived cell lines. The effect of ChoKα inhibitors in combination with 5-FU as a new alternative for the treatment of colon tumors has been investigated both in vitro in CRC-tumour derived cell lines, and in vivo in mouse xenografts models. The effects on thymidilate synthase (TS) and thymidine kinase (TK1) levels, two enzymes known to play an essential role in the mechanism of action of 5-FU, were analyzed by western blotting and quantitative PCR analysis. The combination of 5-FU with ChoKα inhibitors resulted in a synergistic effect in vitro in three different human colon cancer cell lines, and in vivo against human colon xenografts in nude mice. ChoKα inhibitors modulate the expression levels of TS and TK1 through inhibition of E2F production, providing a rational for its mechanism of action.CONCLUSION/SIGNIFICANCEOur data suggest that both drugs in combination display a synergistic antitumoral effect due to ChoKα inhibitors-driven modulation of the metabolization of 5-FU. The clinical relevance of these findings is strongly supported since TCD-717 has recently entered Phase I clinical trials against solid tumors.

100 项与 TCD-717 相关的药物交易

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