Siremadlin free base · Synonyms: NVP-HDM201 | HDM201

Siremadlin is a potent and highly specific MDM-2/p53 inhibitor.

For research use only. Not for human or veterinary use.

Target MDM-2/p53 E1/E2/E3 Enzyme

Research area Cancer

Purity >98% Stock Inquire

Data Sheet SDS COA

Siremadlin structure

CAS No.: 1448867-41-1

Download structure (.mol)

Pack sizes & pricing

Size	Price	SKU	Stock
100 mg	USD 450.00	BP-02135-100mg	In stock	Get quote
250 mg	USD 880.00	BP-02135-250mg	In stock	Get quote
500 mg	USD 1,380.00	BP-02135-500mg	Inquire	Get quote
1 g	USD 2,200.00	BP-02135-1g	In stock	Get quote

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Description

Siremadlin (NVP-HDM201) is a potent and highly specific MDM-2/p53 inhibitor.

Biological activity

In Vitro Siremadlin (NVP-HDM201) disrupts both human and murine TP53- MDM2 interactions, with nanomolar cellular IC50 values, blocking TP53 degradation. In Vivo Siremadlin (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 Siremadlin (NVP-HDM201). Sixteen out of 21 allograft models are sensitive to Siremadlin (NVP-HDM201) but ultimately relapse under treatment. A comparison of tumors with acquired resistance to Siremadlin (NVP-HDM201) and untreated tumors identified 87 genes that are differentially and significantly targeted by the PB transposon[1]. Siremadlin (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 Siremadlin (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 Siremadlin (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.

Identifiers

SMILES: COC1=NC(OC)=C(C=N1)C1=NC2=C([C@@H](N(C2=O)C2=CC(Cl)=CN(C)C2=O)C2=CC=C(Cl)C=C2)N1C(C)C
InChIKey: AGBSXNCBIWWLHD-FQEVSTJZSA-N

Specifications

MW (average): 555.4130
Formula: C₂₆H₂₄Cl₂N₆O₄
CAS No.: 1448867-41-1
Physical state: Solid
Color: White to off-white
Shipping: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage: Powder -20℃ 2 years; In solvent -20℃ 1 month;

Solubility

Soluble in DMSO > 50mg/mL

Documents

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]. Holzer, Philipp. “Discovery of Potent and Selective p53-MDM2 Protein-Protein Interaction Inhibitors as Anticancer Drugs.” Chimia vol. 71,10 (2017): 716-721.

Same target

Search MDM-2/p53

Same research area

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