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MedKoo Cat#: 206159 | Name: Siremadlin free base
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Description:

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

Siremadlin (HDM201) is a potent and selective MDM2 antagonist designed to reactivate p53 signaling in tumors with wild-type TP53. It binds to MDM2 with high affinity (IC₅₀ ≈ 2.1 nM), disrupting the MDM2–p53 interaction and leading to p53 stabilization, upregulation of p53 target genes (such as p21 and PUMA), and induction of cell cycle arrest and apoptosis in cancer cells. In vitro studies demonstrate antiproliferative activity across a range of wild-type TP53 tumor cell lines, with GI₅₀ values typically in the low nanomolar range. In vivo, Siremadlin has shown robust tumor growth inhibition and regression in xenograft models, including acute myeloid leukemia (AML) and solid tumors like liposarcoma and neuroblastoma.

Chemical Structure

Siremadlin free base
Siremadlin free base
CAS#1448867-41-1 (free base)

Theoretical Analysis

MedKoo Cat#: 206159

Name: Siremadlin free base

CAS#: 1448867-41-1 (free base)

Chemical Formula: C26H24Cl2N6O4

Exact Mass: 554.1236

Molecular Weight: 555.42

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 750.00 2 Weeks
100mg USD 1,250.00 2 Weeks
200mg USD 2,050.00 2 Weeks
500mg USD 2,950.00 2 Weeks
1g USD 3,850.00 2 Weeks
2g USD 6,950.00 2 Weeks
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Related CAS #
1638193-48-2 (succinate) 1448867-41-1 (free base)
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
View handling instruction
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/
Solvent mg/mL mM
Solubility
DMF 20.0 36.01
DMSO 10.0 18.00
Ethanol 15.0 27.01
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

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.

Recalculate based on batch purity %
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.
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: Witkowski J, Polak S, Rogulski Z, Pawelec D. In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part I. Int J Mol Sci. 2022 Oct 26;23(21):12984. doi: 10.3390/ijms232112984. PMID: 36361773; PMCID: PMC9656205. 3: Witkowski J, Polak S, Rogulski Z, Pawelec D. In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part II. Int J Mol Sci. 2022 Oct 8;23(19):11939. doi: 10.3390/ijms231911939. PMID: 36233247; PMCID: PMC9570053. 4: Abdul Razak AR, Bauer S, Suarez C, Lin CC, Quek R, Hütter-Krönke ML, Cubedo R, Ferretti S, Guerreiro N, Jullion A, Orlando EJ, Clementi G, Sand Dejmek J, Halilovic E, Fabre C, Blay JY, Italiano A. Co-Targeting of MDM2 and CDK4/6 with Siremadlin and Ribociclib for the Treatment of Patients with Well-Differentiated or Dedifferentiated Liposarcoma: Results from a Proof-of-Concept, Phase Ib Study. Clin Cancer Res. 2022 Mar 15;28(6):1087-1097. doi: 10.1158/1078-0432.CCR-21-1291. PMID: 34921024. 5: 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. 6: Wu CE, Huang CY, Chen CP, Pan YR, Chang JW, Chen JS, Yeh CN, Lunec J. WIP1 Inhibition by GSK2830371 Potentiates HDM201 through Enhanced p53 Phosphorylation and Activation in Liver Adenocarcinoma Cells. Cancers (Basel). 2021 Jul 31;13(15):3876. doi: 10.3390/cancers13153876. PMID: 34359777; PMCID: PMC8345393. 7: Guerreiro N, Jullion A, Ferretti S, Fabre C, Meille C. Translational Modeling of Anticancer Efficacy to Predict Clinical Outcomes in a First-in-Human Phase 1 Study of MDM2 Inhibitor HDM201. AAPS J. 2021 Feb 7;23(2):28. doi: 10.1208/s12248-020-00551-z. PMID: 33554304. 8: 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. 9: Konopleva M, Martinelli G, Daver N, Papayannidis C, Wei A, Higgins B, Ott M, Mascarenhas J, Andreeff M. MDM2 inhibition: an important step forward in cancer therapy. Leukemia. 2020 Nov;34(11):2858-2874. doi: 10.1038/s41375-020-0949-z. Epub 2020 Jul 10. PMID: 32651541. 10: Decaudin D, Frisch Dit Leitz E, Nemati F, Tarin M, Naguez A, Zerara M, Marande B, Vivet-Noguer R, Halilovic E, Fabre C, Jochemsen A, Roman-Roman S, Alsafadi S. Preclinical evaluation of drug combinations identifies co-inhibition of Bcl-2/XL/W and MDM2 as a potential therapy in uveal melanoma. Eur J Cancer. 2020 Feb;126:93-103. doi: 10.1016/j.ejca.2019.12.012. Epub 2020 Jan 9. Erratum in: Eur J Cancer. 2023 May;184:199. doi: 10.1016/j.ejca.2023.02.004. PMID: 31927215. 11: 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.