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MedKoo Cat#: 408098 | Name: MD-224
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Description:

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

MD-224 is a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression. MD-224 effectively induces rapid degradation of MDM2 at concentrations <1 nM in human leukemia cells. It achieves an IC50 value of 1.5 nM in inhibition of growth of RS4;11 cells and also low nanomolar IC50 values in a panel of leukemia cell lines. MD-224 achieves complete and durable tumor regression in vivo in the RS4;11 xenograft tumor model in mice at well-tolerated dose schedules. MD-224 is thus a highly potent and efficacious MDM2 degrader and warrants extensive evaluations as a new class of anticancer agent.

Chemical Structure

MD-224
MD-224
CAS#2136247-12-4 (free base)

Theoretical Analysis

MedKoo Cat#: 408098

Name: MD-224

CAS#: 2136247-12-4 (free base)

Chemical Formula: C48H43Cl2FN6O6

Exact Mass: 888.2605

Molecular Weight: 889.81

Elemental Analysis: C, 64.79; H, 4.87; Cl, 7.97; F, 2.14; N, 9.44; O, 10.79

Price and Availability

Size Price Availability Quantity
1mg USD 90.00 Ready to ship
5mg USD 225.00 Ready to ship
10mg USD 400.00 Ready to ship
25mg USD 850.00 Ready to ship
50mg USD 1,450.00 Ready to ship
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Related CAS #
2136247-12-4 (free base) MD-224 HCl
Synonym
MD-224; MD 224; MD224;
IUPAC/Chemical Name
(3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-(4-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)carbamoyl)phenyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide
InChi Key
ZLGNYFOIDAVMHY-MPKOGUQCSA-N
InChi Code
InChI=1S/C48H43Cl2FN6O6/c49-29-16-19-34-36(25-29)54-46(63)48(34)39(32-12-8-13-35(50)40(32)51)41(56-47(48)22-4-2-5-23-47)44(61)53-30-17-14-28(15-18-30)42(59)52-24-6-1-3-9-27-10-7-11-31-33(27)26-57(45(31)62)37-20-21-38(58)55-43(37)60/h7-8,10-19,25,37,39,41,56H,1-2,4-6,20-24,26H2,(H,52,59)(H,53,61)(H,54,63)(H,55,58,60)/t37?,39-,41+,48+/m0/s1
SMILES Code
FC1=C(Cl)C=CC=C1[C@@H]2[C@@]3(C(C=CC(Cl)=C4)=C4NC3=O)C5(CCCCC5)N[C@H]2C(NC6=CC=C(C(NCCCC#CC7=C(CN(C8C(NC(CC8)=O)=O)C9=O)C9=CC=C7)=O)C=C6)=O
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
Shelf Life
>3 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
Human murine double minute 2 (MDM2) protein is a primary endogenous cellular inhibitor of the tumor suppressor p53 and has been pursued as an attractive cancer therapeutic target. Several potent, nonpeptide, small-molecule inhibitors of MDM2 are currently in clinical development
Biological target:
MD-224 is a first-in-class and highly potent small-molecule human murine double minute 2 (MDM2) degrader.
In vitro activity:
MD-224 was first examined for its potency in induction of MDM2 depletion and p53 activation in the RS4;11 and MV4;11 leukemia cell lines. Treatment of the RS4;11 cells MD-224 for 2 h effectively induces depletion of MDM2 protein and currently accumulation of p53 protein in a dose-dependent manner (Figure 9A). Consistent with their high potency in inhibition of cell growth, MD-224 effectively induces marked depletion of MDM2 protein at concentrations ⩽ 1 nM and MD-224 is more potent than MD-222. The MDM2 inhibitor MI-1061 induces accumulation of both MDM2 and p53 proteins, consistent with its mechanism of action as a potent MDM2 inhibitor. MD-224 is similarly potent and effective in inducing depletion of MDM2 protein and accumulation of p53 protein in MV4;11 cell line (Figure 9B), when compared to RS4;11 cell line. Reference: J Med Chem. 2019 Jan 24;62(2):448-466. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30525597/
In vivo activity:
The pharmacodynamic (PD) effect of MD-224 in vivo was investigated in mice bearing the RS4;11 xenograft tumor (Figure 14). A single, intravenous dose of MD-224 effectively depletes MDM2 protein at the 3 h time point, with the effect persisting for >24 h (Figure 14). MD-224 induces strong upregulation of p53 and p21 at the 3 h time-point in the tumor tissue with the effect lasting for >24 h. PARP cleavage is evident at the 24 h time point, indicating induction of apoptosis. The PD data thus show that by degradation of MDM2 protein, a single dose of the MDM2 degrader MD-224 can achieve robust and sustained MDM2 degradation and p53 upregulation for >24 h. Previous data showed that a single dose of our potent MDM2 inhibitor MI-77301 can upregulate p53 protein for only a few hours from tumor tissue in mice13, likely due to robust accumulation of MDM2 protein, which can bind to and rapidly degrade p53 once the MDM2 inhibitor is cleared from the tumor tissue. The sustained p53 protein accumulation by MD-224 suggests that infrequent (e.g. weekly) administration may be sufficient to achieve strong antitumor activity. Reference: J Med Chem. 2019 Jan 24;62(2):448-466. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30525597/
Solvent mg/mL mM
Solubility
DMSO 100.0 112.38
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 889.81 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:
In vitro protocol:
1. Li Y, Yang J, Aguilar A, McEachern D, Przybranowski S, Liu L, Yang CY, Wang M, Han X, Wang S. Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression. J Med Chem. 2019 Jan 24;62(2):448-466. doi: 10.1021/acs.jmedchem.8b00909. Epub 2018 Dec 10. PMID: 30525597; PMCID: PMC6545112.
In vivo protocol:
1. Li Y, Yang J, Aguilar A, McEachern D, Przybranowski S, Liu L, Yang CY, Wang M, Han X, Wang S. Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression. J Med Chem. 2019 Jan 24;62(2):448-466. doi: 10.1021/acs.jmedchem.8b00909. Epub 2018 Dec 10. PMID: 30525597; PMCID: PMC6545112.
1: Li Y, Yang J, Aguilar A, McEachern D, Przybranowski S, Liu L, Yang CY, Wang M, Han X, Wang S. Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression. J Med Chem. 2019 Jan 24;62(2):448-466. doi: 10.1021/acs.jmedchem.8b00909. Epub 2018 Dec 10. PubMed PMID: 30525597; PubMed Central PMCID: PMC6545112.