HDM201 (Siremadlin) HCl

Alias: HDM-201; HDM 201; HDM201; NVP-HDM 201; NVP-HDM201; NVP-HDM-201

Cat No.:V3166 Purity: ≥98%

COA Product Data Instructions for use SDS

HDM201 HCl (also called Siremadlin;NVP-HDM201, HDM stands for human double minute 2 homolog) is an orally bioavailable, highly potent and selective inhibitor of the p53-Mdm2 protein-protein interaction.

HDM201 (Siremadlin) HCl Chemical Structure CAS No.: 1448867-42-2
Product category: Mdm2

This product is for research use only, not for human use. We do not sell to patients.

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1-708-310-1919 sales@invivochem.com

Other Forms of HDM201 (Siremadlin) HCl:

Siremadlin

Official Supplier of:

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Purity & Quality Control Documentation

Current batch：

Purity: ≥98%

COA

MSDS

Instructions

Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Clinical Trial Information
Biological Data

Product Description

HDM201 HCl (also called Siremadlin; NVP-HDM201, HDM stands for 'human double minute 2 homolog') is an orally bioavailable, highly potent and selective inhibitor of the p53-Mdm2 protein-protein interaction that is orally bioavailable. It has a selectivity ratio of more than 1000-fold against Mdm4 and a high affinity for Mdm2 in the picomolar range. A phase I clinical trial using HDM201 is currently being conducted to treat cancer. The HDM2 protein's ability to bind to the p53 tumor suppressor protein's transcriptional activation domain is inhibited by HDM201. The proteosome-mediated enzymatic degradation of p53 is inhibited by preventing this HDM2-p53 protein-protein interaction, which restores both p53 signaling and p53-mediated induction of tumor cell apoptosis.

Biological Activity I Assay Protocols (From Reference)

ln Vitro

In vitro activity: HDM201 acts by binding to the p53 binding-site of the Mdm2 protein, thereby disrupting the interaction of the two proteins (p53 and Mdm2) and leading to the activation of the p53 pathway. In human tumor cells with p53 wild-type, it causes a robust cell cycle arrest and apoptosis. A panel of cancer cell lines that HDM201 exhibits high selectivity toward.

ln Vivo

Treatment was initiated when the tumors engrafted in the flank were at least 150 mm3. The enrollment process was random. With the measurements of tumor volumes at the beginning of treatment, efficacy studies, tumor response, and relapse were reported. Two times per week, at intervals of 3 days and 4 days alternately, HDM201 was given orally at a dose of 100 mg/kg in a solution of 0.5% methylcellulose and 0.1% Tween 80. Vehicle was produced using the formulation. Early in the morning, treatments were given.

Cell Assay

The in vitro combination screen was carried out on cancer cell lines at Horizon Discovery (Cambridge, MA), and data analysis was done as previously mentioned. Here, we concentrated our data analysis on combinations involving CGM097, a member of an earlier generation of selective TP53-MDM2 inhibitors. Various concentrations of CGM097 and 25 additional compounds were applied to a total of 485 cancer cell lines. We combined the data on TP53 mutation status and distinguished between cell lines that did not have TP53 mutations and cell lines that did. We evaluated the synergistic effects of combining HDM201 and A-1155463 as previously mentioned.

Animal Protocol

HDM201 was administered at 100 mg/kg in 0.5% methylcellulose and 0.1% Tween 80 orally twice a week

Mouse

References

[1]. Bioorg Med Chem Lett. 2016 Oct 1;26(19):4837-4841.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula	C26H24CL2N6O4
Molecular Weight	555.41
Exact Mass	554.123
CAS #	1448867-42-2
Related CAS #	Siremadlin;1448867-41-1
PubChem CID	71679278
Appearance	Typically exists as solid at room temperature
LogP	3.6
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	6
Heavy Atom Count	38
Complexity	987
Defined Atom Stereocenter Count	1
SMILES	CC(C)N1C2=C(C(=O)N([C@@H]2C3=CC=C(C=C3)Cl)C4=CC(=CN(C4=O)C)Cl)N=C1C5=CN=C(N=C5OC)OC
InChi Key	AGBSXNCBIWWLHD-HXUWFJFHSA-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-/m1/s1
Chemical Name	(4R)-5-(5-chloro-1-methyl-2-oxopyridin-3-yl)-4-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-6-one
Synonyms	HDM-201; HDM 201; HDM201; NVP-HDM 201; NVP-HDM201; NVP-HDM-201
HS Tariff Code	2934.99.9001
Storage	Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility Data

Solubility (In Vitro)

DMSO: ~100 mg/mL (~180.0 mM)

Water: < 1mg/mL

Ethanol: ~3 mg/mL (~5.4 mM)

Solubility (In Vivo)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

Injection Formulations
(e.g. IP/IV/IM/SC)

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

Oral Formulations

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		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	0.1800 mL	0.9002 mL	1.8005 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

Calculator

Mass

Concentration

Volume

Molecular Weight*

Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

Calculate the Mass of a compound required to prepare a solution of known volume and concentration
Calculate the Volume of solution required to dissolve a compound of known mass to a desired concentration
Calculate the Concentration of a solution resulting from a known mass of compound in a specific volume

See Example

An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

Enter 350.26 in the Molecular Weight (MW) box
Enter 10 in the Concentration box and choose the correct unit (mM)
Enter 5 in the Volume box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

Concentration (Start)

Volume (Start)

Concentration (End)

Volume (End)

Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
Enter 25 into the Concentration (End) box and select the correct unit (mM)
Enter 25 into the Volume (End) box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

Molecular formula

Total molecular weight

g/mol

Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4 c12h18n3o4
Instructions to calculate molar mass (molecular weight) of a chemical compound:

To calculate molar mass of a chemical compound, please enter the chemical/molecular formula and click the “Calculate’ button.

Definitions of molecular mass, molecular weight, molar mass and molar weight:

Molecular mass (or molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.

Volume (to add to vial)

Mass (in vial)

Desired Reconstitution Concentration

Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

Enter the mass of the reagent and the desired reconstitution concentration as well as the correct units
Click the “Calculate” button
The answer appears in the Volume (to add to vial) box

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

Dosage mg/kg

Average weight of animals g

Dosing volume per animal μL

Number of animals

Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)

% DMSO

% Tween 80

% ddH₂O

Calculation results

Working concentration： mg/mL；

Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O，mix and clarify.

Note： (1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.

Clinical Trial Information

NCT Number	Recruitment	interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT03940352	Active Recruiting	Drug: HDM201 Drug: Venetoclax	Acute Myeloid Leukemia (AML) High-risk Myelodysplastic Syndrome (MDS)	Novartis Pharmaceuticals	June 24, 2019	Phase 1
NCT05599932	Recruiting	Drug: Siremadlin	Hepatic Impairment	Novartis Pharmaceuticals	December 2, 2022	Phase 1
NCT05180695	Recruiting	Drug: Pazopanib Drug: HDM201	Advanced Soft-tissue Sarcoma Metastatic Soft-tissue Sarcoma	Centre Leon Berard	April 15, 2022	Phase 1 Phase 2
NCT03714958	Completed	Drug: HDM201 Drug: Trametinib	Colorectal Cancer Advanced Cancer	Centre Leon Berard	December 20, 2018	Phase 1
NCT02343172	Completed	Drug: HDM201 Drug: LEE011	Liposarcoma	Novartis Pharmaceuticals	March 13, 2015	Phase 1

Biological Data

Bcl-xL modulates the sensitivity of cell lines to TP53-MDM2 inhibition.Proc Natl Acad Sci U S A.2017 Mar 21;114(12):3151-3156.
Bcl-xL expression confers resistance to HDM201.Proc Natl Acad Sci U S A.2017 Mar 21;114(12):3151-3156.
Characterization of genetic modifications in HDM201-resistant tumors.Proc Natl Acad Sci U S A.2017 Mar 21;114(12):3151-3156.
Response and resistance to HDM201 TP53-MDM2 inhibitor allografted mice.Proc Natl Acad Sci U S A.2017 Mar 21;114(12):3151-3156.
Characterization of response to HDM201 treatment of RosaPB/+;ATP2/+;Arf−/−allografted tumors.Proc Natl Acad Sci U S A.2017 Mar 21;114(12):3151-3156.

Resistance mechanisms identified in HDM201-resistant tumors.Representation of major PB transposon insertions found significantly enriched in RosaPB/+;ATP2/+;Arf−/−HDM201-resistant implanted tumors compared with untreated tumors (n= 95 tumors with differential PB insertions).Proc Natl Acad Sci U S A.2017 Mar 21;114(12):3151-3156.