Name: MD-224
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥95%

Solubility

Soluble in DMSO

Appearance

Solid Powder

Storage

Store at 2-8°C for short term (days to weeks) or -20°C for long term (months to years)

IUPACName

(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

Synonyms

(3'R,4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-N-[4-({5-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-4-pentyn-1-yl}carbamoyl)phenyl]-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide; MD 224; MD224; Dispiro[cyclohexane-1,2'-pyrrolidine-3',3''-[3H]indole]-5'-carboxamide, 6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-[4-[[[5-[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-4-yl]-4-pentyn-1-yl]amino]carbonyl]phenyl]-1'',2''-dihydro-2''-oxo-, (3'R,4'S,5'R)-; (3'R,4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-N-[4-[[[5-[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-4-yl]-4-pentyn-1-yl]amino]carbonyl]phenyl]-1'',2''-dihydro-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-[3H]indole]-5'-carboxamide

Density

1.49±0.1 g/cm3

InChI Key

ZLGNYFOIDAVMHY-MPKOGUQCSA-N

InChI

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

C1CCC2(CC1)C3(C(C(N2)C(=O)NC4=CC=C(C=C4)C(=O)NCCCC#CC5=C6CN(C(=O)C6=CC=C5)C7CCC(=O)NC7=O)C8=C(C(=CC=C8)Cl)F)C9=C(C=C(C=C9)Cl)NC3=O

Mechanism

Target: MD-224 selectively targets human MDM2, the p53-regulating E3 ubiquitin ligase.

Binding site: Its MDM2 ligand engages the N-terminal p53-binding hydrophobic cleft.

Mechanism of action: MD-224 is a first-in-class, highly potent small-molecule MDM2 PROTAC degrader based on cereblon recruitment. The molecule contains an MDM2-binding ligand connected to a CRBN ligand, enabling MDM2 recruitment to CRL4CRBN ubiquitin ligase machinery and subsequent proteasome-dependent degradation. Depletion of MDM2 can stabilize and activate p53 signaling in experimental systems with functional p53. MD-224 is useful for studying MDM2 turnover, p53 pathway regulation, degradation potency, ternary-complex-dependent pharmacology, and differences between MDM2 antagonism and direct MDM2 protein removal.

Applications

• PROTAC-Mediated Kinase Degradation: MD-224 is utilized in research to selectively degrade kinases implicated in cancer progression. By harnessing the ubiquitin-proteasome system, this PROTAC facilitates the targeted degradation of specific kinase proteins, offering insights into their biological roles and potential for therapeutic intervention.

• Targeted Protein Degradation in Drug Discovery: Researchers employ MD-224 to explore novel avenues in drug discovery, focusing on the degradation of previously "undruggable" targets. This PROTAC enables the investigation of protein function and validation of new targets, advancing the understanding of complex disease mechanisms.

• E3 Ligase Recruitment Studies: MD-224 serves as a tool to study the recruitment of E3 ligases in the context of targeted protein degradation. By examining the interaction dynamics between PROTACs, E3 ligases, and target proteins, researchers can optimize the design of more efficient degraders.

• Mechanistic Studies of Protein Degradation: MD-224 is instrumental in elucidating the mechanisms underlying PROTAC-induced protein degradation. Through detailed mechanistic studies, researchers can dissect the pathways and processes involved, enhancing the development of targeted degradation strategies for various diseases.

1. 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.

Li, Y., Yang, J., Aguilar, A., McEachern, D., Przybranowski, S., Liu, L., Yang, C.Y., Wang, M., Han, X. and Wang, S., 2018. Journal of medicinal chemistry, 62(2), pp.448-466.

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. In this paper, we report our design, synthesis, and evaluation of small-molecule MDM2 degraders based on the proteolysis targeting chimera (PROTAC) concept. The most promising compound (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.

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