MD-222
目录号 : GC62716
MD-222 是一种首创的高效的基于 PROTAC 的 MDM2 降解剂。MD-222 诱导 MDM2 蛋白快速降解并激活细胞中的野生型 p53。MD-222 具有抗癌作用。
Cas No.:2136246-72-3
Sample solution is provided at 25 µL, 10mM.
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- Purity: >99.00%
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MD-222 is the first-in-class highly potent PROTAC degrader of MDM2. MD-222 induces rapid degradation of the MDM2 protein and activation of wild-type p53 in cells. MD-222 has anticancer effects[1][2].
MD-222 (1-30 nM; 1-2 hours) treatment shows very effective in reducing the levels of MDM2 protein and increasing the levels of p53 in a time- and dose-dependent manner in RS4;11 and RS4;11/IRMI-2 cells[1]. MD-222 (30-100 nM; 6 hours) is effective in increasing the expression of several p53-targeted genes, such as MDM2, CDKN1A, and PUMA in RS4;11 cells, indicating strong activation of p53[2]. MD-222 (4 days) shows cell growth inhibitory activity in RS4;11 cells with an IC50 of 5.5 nM, and has no effect on RS4;11/IRMI-2, MDA-MB-231 and MDA-MB-468 cells[1].
[1]. Jiuling Yang, et al. Simple Structural Modifications Converting a Bona fide MDM2 PROTAC Degrader into a Molecular Glue Molecule: A Cautionary Tale in the Design of PROTAC Degraders. J Med Chem. 2019 Nov 14;62(21):9471-9487.
[2]. Li Y, et al. Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis TargetingChimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable TumorRegression. J Med Chem. 2019 Jan 24;62(2):448-466.
Cas No. | 2136246-72-3 | SDF | |
分子式 | C48H47Cl2FN6O6 | 分子量 | 893.83 |
溶解度 | DMSO : 200 mg/mL (223.76 mM; Need ultrasonic) | 储存条件 | -20°C, away from moisture |
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1 mg | 5 mg | 10 mg |
1 mM | 1.1188 mL | 5.5939 mL | 11.1878 mL |
5 mM | 0.2238 mL | 1.1188 mL | 2.2376 mL |
10 mM | 0.1119 mL | 0.5594 mL | 1.1188 mL |
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Simple Structural Modifications Converting a Bona fide MDM2 PROTAC Degrader into a Molecular Glue Molecule: A Cautionary Tale in the Design of PROTAC Degraders
J Med Chem 2019 Nov 14;62(21):9471-9487.PMID:31560543DOI:PMC7354697
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 by MG-277. MG-277 induces 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 that MG-277 is 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.