Name: MD-222
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

99%

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)pentyl)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]pentyl}carbamoyl)phenyl]-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide; MD 222; MD222; 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]pentyl]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]pentyl]amino]carbonyl]phenyl]-1'',2''-dihydro-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-[3H]indole]-5'-carboxamide

Density

1.46±0.1 g/cm3

InChI Key

RRSNDVCODIMOFX-MPKOGUQCSA-N

InChI

InChI=1S/C48H47Cl2FN6O6/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,1-6,9,20-24,26H2,(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)NCCCCCC5=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-222 selectively targets MDM2, the E3 ligase regulator of p53.

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

Mechanism of action: MD-222 is a cereblon-recruiting MDM2 PROTAC designed to induce rapid degradation of MDM2 and thereby activate wild-type p53 signaling. The compound combines an MDM2-binding ligand with a CRBN ligand, enabling MDM2 recruitment to CRL4CRBN ubiquitin ligase machinery. This induced-proximity mechanism promotes MDM2 ubiquitination and proteasome-dependent depletion, reducing the abundance of the negative p53 regulator. In research applications, MD-222 supports studies of MDM2 dependency, p53 pathway reactivation, degradation kinetics, and mechanistic differences between MDM2 antagonism and physical removal of MDM2 protein.

Applications

• PROTAC-Mediated Targeted Degradation: MD-222 is designed to facilitate the targeted degradation of specific proteins within cellular environments. By harnessing the ubiquitin-proteasome system, this PROTAC molecule selectively tags target proteins for degradation, enabling researchers to study protein function and regulation in a controlled manner.

• Protein Interaction Studies via PROTACs: Utilizing MD-222 allows for the investigation of protein-protein interactions by degrading one protein partner and observing the resultant effects. This application is crucial for understanding complex signaling pathways and identifying potential therapeutic targets.

• Functional Protein Knockdown: MD-222 provides an innovative approach to functional protein knockdown, offering an alternative to traditional gene knockdown techniques. This PROTAC facilitates the rapid and efficient removal of target proteins, allowing researchers to study the immediate consequences of protein loss in cellular models.

• Selective Protein Degradation Research: MD-222 serves as a powerful tool for selective protein degradation research, enabling the exploration of degradation pathways and mechanisms. Researchers can apply this PROTAC to dissect the roles of specific proteins in disease models and cellular processes.

1. Simple Structural Modifications Converting a Bona fide MDM2 PROTAC Degrader into a Molecular Glue Molecule: A Cautionary Tale in the Design of PROTAC Degraders

Angelo Aguilar, Yangbing Li, Shaomeng Wang, Jiuling Yang, Chao-Yie Yang, Zhaomin Liu J Med Chem . 2019 Nov 14;62(21):9471-9487. doi: 10.1021/acs.jmedchem.9b00846.

Inducing protein degradation by proteolysis targeting chimeras (PROTACs) has gained tremendous momentum for its promise to discover and develop new therapies. Based upon our previously reported PROTAC MDM2 degraders, we have designed and synthesized additional analogues. Surprisingly, we found that simple structural modifications of MD-222, a bona fide MDM2 PROTAC degrader, converts it into a "molecular glue", as exemplified byMG-277.MG-277induces only moderate MDM2 degradation and fails to activate wild-type p53 but is highly potent in inhibition of tumor cell growth in a p53-independent manner. Our mechanistic investigation established thatMG-277is not a PROTAC MDM2 degrader but instead works as a molecular glue, inducing degradation of a translation termination factor, GSPT1 to achieve its potent anticancer activity. Our study provides the first example that simple structural modifications can convert a bona fide PROTAC degrader into a molecular glue compound, which has a completely different mechanism of action.

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Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂