NVP-HDM201 (HDM201) 是高效,选择性,在临床I期试验中的 MDM-2/p53 抑制剂。
Description | NVP-HDM201 (HDM201) is a potent and highly specific MDM-2/p53 inhibitor currently under phase I clinical trial. | ||||||||||||||||
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In Vitro | NVP-HDM201 disrupts both human and murine TP53- MDM2 interactions, with nanomolar cellular IC50 values, blocking TP53 degradation[1]. | ||||||||||||||||
In Vivo | NVP-HDM201 is an imidazolopyrrolidinone analogue, showing a very advantageous in vivo profile. NVP-HDM201 has recently entered Phase 1 clinical trials in cancer patients[2]. Constitutive PB mutagenesis in Arf−/− mice provides a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors are allografted in large cohorts of mice to assess the pharmacologic effects of NVP-HDM201. Sixteen out of 21 allograft models are sensitive to NVP-HDM201 but ultimately relapse under treatment. A comparison of tumors with acquired resistance to NVP-HDM201 and untreated tumors identified 87 genes that are differentially and significantly targeted by the PB transposon[1]. NVP-HDM201 administered either daily at a low dose or once at a high dose revealed a differentiated engagement of the p53 molecular response. In contrast to the daily low dose treatment regimen, the single high dose NVP-HDM201 regimen results in a rapid and dramatic induction of p53-dependent PUMA expression and apoptosis. This is consistent with the finding that a single high dose NVP-HDM201 treatment, administered orally or intravenously, results in a robust and sustained tumor regression. Overall, both daily and once every 3 weeks dosing regimen shows comparable long term efficacy in preclinical studies. The ongoing clinical trial is currently designed to compare both dosing regimens with regard to efficacy and tolerability[3]. | ||||||||||||||||
Solvent & Solubility | In Vitro: DMSO : ≥ 56.75 mg/mL (102.18 mM) * "≥" means soluble, but saturation unknown. Preparing Stock Solutions
* Please refer to the solubility information to select the appropriate solvent. | ||||||||||||||||
References | |
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