Siremadlin | CAS#1448867-41-1 | HMD2 inhibitor

Siremadlin
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WARNING: This product is for research use only, not for human or veterinary use.

MedKoo CAT#: 206159

CAS#: 1448867-41-1

Description: Siremadlin, also known as HDM201, is an orally bioavailable human double minute 2 homolog (HDM2) inhibitor with potential antineoplastic activity. HDM2 inhibitor HDM201 inhibits the binding of the HDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. HDM2, a zinc finger protein and negative regulator of the p53 pathway, is often overexpressed in cancer cells and has been implicated in cancer cell proliferation and survival.

Chemical Structure

Siremadlin

CAS# 1448867-41-1

Product data Instruction

Theoretical Analysis

MedKoo Cat#: 206159
Name: Siremadlin
CAS#: 1448867-41-1
Chemical Formula: C26H24Cl2N6O4
Exact Mass: 554.12
Molecular Weight: 555.420
Elemental Analysis: C, 56.23; H, 4.36; Cl, 12.77; N, 15.13; O, 11.52

Price and Availability

Size	Price	Availability	Quantity
50mg	USD 750
100mg	USD 1250
200mg	USD 2050
500mg	USD 2950
1g	USD 3850
2g	USD 6950
Bulk inquiry Welcome, Customer: Please do not inquire quote if your intended use is for a patient since our products are for research use and for chemical synthesis use, not for human use . For in-stock products, we listed price in the web page. You may inquire prices for which sizes were not listed. If no price is listed, this means the product is not in stock at the moment, which may be available via custom synthesis. For cost-effective reason, minimum order of 1g is requested (typically very expensive). The lead time is usually 2-4 months. Quote of less than 1g will not be provided. MedKoo may not offer quote for below reasons: (1) current available synthetic method appears to be extremely expensive which is obviously not affordable to most customers; (2) Key raw material to make the product is temporally not available; (3) DEA controlled substances; (4) the product is under patent protection in customer’s country.

Synonym: Siremadlin; HDM201; HDM 201; HDM-201; NVP-HDM201; NVP-HDM-201; NVP-HDM 201.

IUPAC/Chemical Name: (6S)-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)-Pyrrolo[3,4-d]imidazol-4(1H)-one

InChi Key: AGBSXNCBIWWLHD-FQEVSTJZSA-N

InChi Code: InChI=1S/C26H24Cl2N6O4/c1-13(2)33-21-19(30-22(33)17-11-29-26(38-5)31-23(17)37-4)25(36)34(18-10-16(28)12-32(3)24(18)35)20(21)14-6-8-15(27)9-7-14/h6-13,20H,1-5H3/t20-/m0/s1

SMILES Code: 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

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: 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 Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, DMF, and ethanol

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info: By preventing this HDM2-p53 interaction, the proteosome-mediated enzymatic degradation of p53 is inhibited, which may result in the restoration of both p53 signaling and p53-mediated induction of tumor cell apoptosis.

Product Data:

Product Data

Instruction:

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Biological target:	Siremadlin is an inhibitor of the protein-protein interaction between the E3 ubiquitin ligase MDM2 and p53 (IC50 = 0.21 nM). It selectively inhibits the MDM2-p53 protein-protein interaction over MDM4-p53, YAP1-TEAD4, PCSK9-LDLR, and Bcl-2-Bak interactions in time-resolved FRET (TR-FRET) assays (IC50s = 3.3, >150, >50, and >50 µM, respectively). Siremadlin inhibits the growth of SJSA-1 osteosarcoma cells (GI50 = 38 nM).
In vitro activity:	Inhibition of MDM2 by siremadlin promotes the antitumor responsed in p53 wild-type cancer cells. In response to HDM201 treatment, the percentage of dendritic cells increased, including the CD103+ antigen cross-presenting subset. Furthermore, HDM201 increased the percentage of Tbet+Eomes+ CD8+ T cells and the CD8+/Treg ratio within the tumor. Reference: Cancer Res. 2021 Jun 1;81(11):3079-3091. https://pubmed.ncbi.nlm.nih.gov/33504557/
In vivo activity:	Siremadlin demonstrates therapeutic efficacy in p53 wild-type cancers. High-dose regimen rapidly induces PUMA, apoptosis, and downregulates Bcl-xL in vivo. Clinical trials suggest reproducibility of pulse dosing's molecular mechanism in patients, supporting the comparison of daily and intermittent regimens for p53-MDM2 inhibitors, such as siremadlin. Reference: Cancer Res. 2018 Nov 1;78(21):6257-6267. https://pubmed.ncbi.nlm.nih.gov/30135191/

Solubility Data

	Solvent	Max Conc. mg/mL	Max Conc. mM
Solubility
	DMF	20.0	36.01
	DMSO	10.0	18.00
	Ethanol	15.0	27.01

Preparing Stock Solutions

The following data is based on the product molecular weight 555.42 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:	1. Witkowski J, Polak S, Pawelec D, Rogulski Z. In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part III. Int J Mol Sci. 2023 Jan 23;24(3):2239. doi: 10.3390/ijms24032239. PMID: 36768563; PMCID: PMC9917191. 2. Wang HQ, Mulford IJ, Sharp F, Liang J, Kurtulus S, Trabucco G, Quinn DS, Longmire TA, Patel N, Patil R, Shirley MD, Chen Y, Wang H, Ruddy DA, Fabre C, Williams JA, Hammerman PS, Mataraza J, Platzer B, Halilovic E. Inhibition of MDM2 Promotes Antitumor Responses in p53 Wild-Type Cancer Cells through Their Interaction with the Immune and Stromal Microenvironment. Cancer Res. 2021 Jun 1;81(11):3079-3091. doi: 10.1158/0008-5472.CAN-20-0189. Epub 2021 Jan 27. PMID: 33504557. 3. Stein EM, DeAngelo DJ, Chromik J, Chatterjee M, Bauer S, Lin CC, Suarez C, de Vos F, Steeghs N, Cassier PA, Tai D, Kiladjian JJ, Yamamoto N, Mous R, Esteve J, Minami H, Ferretti S, Guerreiro N, Meille C, Radhakrishnan R, Pereira B, Mariconti L, Halilovic E, Fabre C, Carpio C. Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors and Acute Leukemia. Clin Cancer Res. 2022 Mar 1;28(5):870-881. doi: 10.1158/1078-0432.CCR-21-1295. PMID: 34862243; PMCID: PMC9377734. 4. Jeay S, Ferretti S, Holzer P, Fuchs J, Chapeau EA, Wartmann M, Sterker D, Romanet V, Murakami M, Kerr G, Durand EY, Gaulis S, Cortes-Cros M, Ruetz S, Stachyra TM, Kallen J, Furet P, Würthner J, Guerreiro N, Halilovic E, Jullion A, Kauffmann A, Kuriakose E, Wiesmann M, Jensen MR, Hofmann F, Sellers WR. Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53-MDM2 Inhibitor HDM201. Cancer Res. 2018 Nov 1;78(21):6257-6267. doi: 10.1158/0008-5472.CAN-18-0338. Epub 2018 Aug 22. PMID: 30135191.
In vitro protocol:	1. Witkowski J, Polak S, Pawelec D, Rogulski Z. In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part III. Int J Mol Sci. 2023 Jan 23;24(3):2239. doi: 10.3390/ijms24032239. PMID: 36768563; PMCID: PMC9917191. 2. Wang HQ, Mulford IJ, Sharp F, Liang J, Kurtulus S, Trabucco G, Quinn DS, Longmire TA, Patel N, Patil R, Shirley MD, Chen Y, Wang H, Ruddy DA, Fabre C, Williams JA, Hammerman PS, Mataraza J, Platzer B, Halilovic E. Inhibition of MDM2 Promotes Antitumor Responses in p53 Wild-Type Cancer Cells through Their Interaction with the Immune and Stromal Microenvironment. Cancer Res. 2021 Jun 1;81(11):3079-3091. doi: 10.1158/0008-5472.CAN-20-0189. Epub 2021 Jan 27. PMID: 33504557.
In vivo protocol:	1. Stein EM, DeAngelo DJ, Chromik J, Chatterjee M, Bauer S, Lin CC, Suarez C, de Vos F, Steeghs N, Cassier PA, Tai D, Kiladjian JJ, Yamamoto N, Mous R, Esteve J, Minami H, Ferretti S, Guerreiro N, Meille C, Radhakrishnan R, Pereira B, Mariconti L, Halilovic E, Fabre C, Carpio C. Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors and Acute Leukemia. Clin Cancer Res. 2022 Mar 1;28(5):870-881. doi: 10.1158/1078-0432.CCR-21-1295. PMID: 34862243; PMCID: PMC9377734. 2. Jeay S, Ferretti S, Holzer P, Fuchs J, Chapeau EA, Wartmann M, Sterker D, Romanet V, Murakami M, Kerr G, Durand EY, Gaulis S, Cortes-Cros M, Ruetz S, Stachyra TM, Kallen J, Furet P, Würthner J, Guerreiro N, Halilovic E, Jullion A, Kauffmann A, Kuriakose E, Wiesmann M, Jensen MR, Hofmann F, Sellers WR. Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53-MDM2 Inhibitor HDM201. Cancer Res. 2018 Nov 1;78(21):6257-6267. doi: 10.1158/0008-5472.CAN-18-0338. Epub 2018 Aug 22. PMID: 30135191.

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1: Wu CE, Esfandiari A, Ho YH, Wang N, Mahdi AK, Aptullahoglu E, Lovat P, Lunec J. Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma. Br J Cancer. 2017 Dec 12. doi: 10.1038/bjc.2017.433. [Epub ahead of print] PubMed PMID: 29235570.

2: Holzer P. Discovery of Potent and Selective p53-MDM2 Protein-Protein Interaction Inhibitors as Anticancer Drugs. Chimia (Aarau). 2017 Oct 25;71(10):716-721. doi: 10.2533/chimia.2017.716. PubMed PMID: 29070416.

3: Chapeau EA, Gembarska A, Durand EY, Mandon E, Estadieu C, Romanet V, Wiesmann M, Tiedt R, Lehar J, de Weck A, Rad R, Barys L, Jeay S, Ferretti S, Kauffmann A, Sutter E, Grevot A, Moulin P, Murakami M, Sellers WR, Hofmann F, Jensen MR. 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. doi: 10.1073/pnas.1620262114. Epub 2017 Mar 6. PubMed PMID: 28265066; PubMed Central PMCID: PMC5373361.

4: Furet P, Masuya K, Kallen J, Stachyra-Valat T, Ruetz S, Guagnano V, Holzer P, Mah R, Stutz S, Vaupel A, Chène P, Jeay S, Schlapbach A. 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):4837-4841. doi: 10.1016/j.bmcl.2016.08.010. Epub 2016 Aug 9. PubMed PMID: 27542305.

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