Tosedostat (CHR-2797) is an inhibitor of aminopeptidases that blocks a critical step in the protein degradation and re-synthesizes intracellular pathway. This orally bioavailable agent has shown promising activity in vitro and in early clinical trials for patients with relapsed/refractory AML (acute myeloid leukaemia) [1]. CHR-2797 demonstrated marked in vitro cytotoxicity in AML samples and strong synergy with Cytarabine (Ara-C), but significantly less cytotoxicity to normal marrow progenitors[2]. Additionally, when given in combination with morphine, tosedostat exerts a synergistic analgesic effect resulting in a reduction of effective dosages required to achieve the same analgesic effect[3]. Tosedostat with capecitabine displayed tolerable toxicity, and prolonged disease control in a subset of patients[4].
Tosedostat/托舍多特 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Candida glabrata ATCC 90030
4 μg/ml
6 h and 24 h
To evaluate the antifungal activity of Tosedostat against Candida glabrata, results showed inhibitory effects.
Antimicrob Agents Chemother. 2014;58(2):1055-62.
Candida albicans SC5314
4 μg/ml
6 h and 24 h
To evaluate the antifungal activity of Tosedostat against Candida albicans, results showed inhibitory effects.
Antimicrob Agents Chemother. 2014;58(2):1055-62.
U937 acute myeloid leukemia cells
1 μM
24 hours
To investigate the inhibitory effect of Tosedostat on peptide degradation in U937 cells, results showed that Tosedostat significantly inhibited the degradation process.
Anal Chem. 2013 May 21;85(10):4991-7.
U937 cells (human acute myeloid leukemia cells)
1, 2, 4, 8, 16 μM
95 days
To evaluate the effect of Tosedostat on peptidase activity in U937 cells. Results showed changes in peptide degradation patterns with drug treatment, with the number of fragment peaks decreasing as dose increased.
Integr Biol (Camb). 2014 Feb;6(2):164-74.
RPMI-8226 cells
1 µM
24 hours
To study the synergistic effect of Tosedostat with HDAC inhibitor CHR-3996, results showed that the combination significantly activates NFκB signaling pathway and induces apoptosis.
Oncotarget. 2015 Jul 10;6(19):17314-27.
H929 cells
1 µM
24 hours
To study the synergistic effect of Tosedostat with HDAC inhibitor CHR-3996, results showed that the combination significantly activates NFκB signaling pathway and induces apoptosis.
Oncotarget. 2015 Jul 10;6(19):17314-27.
Tosedostat/托舍多特 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NOD/SCID IL2Rγ-/- mice
Multiple myeloma xenograft model
Intra-peritoneal injection
75 mg/kg
Daily administration for up to 28 days
To study the in vivo synergistic effect of Tosedostat with HDAC inhibitor CHR-3996, results showed that the combination significantly inhibits tumor growth.
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