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| Cas No.: | 1448867-41-1 |
| Chemical Name: | NVP-HDM201 |
| Synonyms: | Pyrrolo[3,4-d]imidazol-4(1H)-one, 5-(5-chloro-1,2-dihydro-1-methyl-2-oxo-3-pyridinyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxy-5-pyrimidinyl)-5,6-dihydro-1-(1-methylethyl)-, (6S)-;Siremadlin |
| 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 |
| Formula: | C26H24Cl2N6O4 |
| M.Wt: | 555.41 |
| Sotrage: | 2 years -20°C Powder, 2 weeks 4°C in DMSO, 6 months -80°C in DMSO |
| Description: | NVP-HDM201 (HDM201) is a potent and highly specific MDM-2/p53 inhibitor currently under phase I clinical trial. |
| 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]. |
| In Vitro: | NVP-HDM201 disrupts both human and murine TP53- MDM2 interactions, with nanomolar cellular IC50 values, blocking TP53 degradation[1]. |