NVP-HDM201
(Synonyms: NVP-HDM201; HDM201) 目录号 : GC19268NVP-HDM201 (NVP-HDM201) 是一种有效的、口服生物利用度高且高度特异性的 p53-MDM2 相互作用抑制剂。
Cas No.:1448867-41-1
Sample solution is provided at 25 µL, 10mM.
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NVP-HDM201 (HDM201) is a potent and highly specific MDM-2/p53 inhibitor currently under phase I clinical trial.
NVP-HDM201 disrupts both human and murine TP53- MDM2 interactions, with nanomolar cellular IC50 values, blocking TP53 degradation[1].
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].
References:
[1]. Chapeau EA, et al. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf-/- mouse model. Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3151-3156.
[2]. Furet P, et al. Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument. Bioorg Med Chem Lett. 2016 Oct 1;26(19):4837-41.
[3]. Stéphane F, et al. Abstract 1224: Insights into the mechanism of action of NVP-HDM201, a differentiated and versatile Next-Generation small-molecule inhibitor of Mdm2, under evaluation in phase I clinical trials. Insights into the mechanism of action of NVP-HDM201, a differentiated and versatile Next-Generation small-molecule inhibitor of Mdm2, under evaluation in phase I clinical trials. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1224.
Cas No. | 1448867-41-1 | SDF | |
别名 | NVP-HDM201; HDM201 | ||
Canonical SMILES | O=C1N(C2=CC(Cl)=CN(C)C2=O)[C@@H](C3=CC=C(Cl)C=C3)C4=C1N=C(C5=CN=C(OC)N=C5OC)N4C(C)C | ||
分子式 | C26H24Cl2N6O4 | 分子量 | 555.41 |
溶解度 | DMSO : ≥ 56.75 mg/mL (102.18 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 1.8005 mL | 9.0024 mL | 18.0047 mL |
5 mM | 0.3601 mL | 1.8005 mL | 3.6009 mL |
10 mM | 0.18 mL | 0.9002 mL | 1.8005 mL |
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% DMSO % % Tween 80 % saline | ||||||||||
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2.
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