Name: SHP2-D26
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

>98%

Solubility

Soluble in DMSO

Appearance

Solid Powder

Storage

Store at -20°C

IUPACName

(2S,4R)-1-[(2S)-2-[9-[4-[4-[3-[3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl]sulfanyl-2-chloroanilino]-4-oxobutanoyl]piperazin-1-yl]nonanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

Synonyms

(2S,4R)-1-((S)-2-(10-(4-(4-((3-((3-Amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)-4-oxobutanoyl)piperazin-1-yl)decanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; SHP2-D 26; PROTAC SHP2 degrader-1

Boiling Point

1240.1±65.0°C at 760 Torr

Density

1.33±0.1 g/cm3

InChI Key

XJSPAQRZSJUBLB-WQFCSRJTSA-N

InChI

InChI=1S/C56H79ClN12O6S2/c1-36(38-17-19-39(20-18-38)49-37(2)61-35-76-49)62-52(74)42-32-40(70)34-69(42)54(75)50(55(3,4)5)65-45(71)16-11-9-7-8-10-12-25-66-28-30-68(31-29-66)47(73)22-21-46(72)63-41-14-13-15-43(48(41)57)77-53-51(58)64-44(33-60-53)67-26-23-56(6,59)24-27-67/h13-15,17-20,33,35-36,40,42,50,70H,7-12,16,21-32,34,59H2,1-6H3,(H2,58,64)(H,62,74)(H,63,72)(H,65,71)/t36-,40+,42-,50+/m0/s1

SMILES

CC1=C(SC=N1)C2=CC=C(C=C2)C(C)NC(=O)C3CC(CN3C(=O)C(C(C)(C)C)NC(=O)CCCCCCCCN4CCN(CC4)C(=O)CCC(=O)NC5=C(C(=CC=C5)SC6=NC=C(N=C6N)N7CCC(CC7)(C)N)Cl)O

Mechanism

Target: Targets SHP2 protein tyrosine phosphatase for experimental targeted protein degradation studies.

Binding Site: Binds the SHP2 allosteric phosphatase pocket and recruited E3 ligase ligand site to support productive ternary complex formation.

Mechanism of Action: SHP2-D26 is designed for use in PROTAC or targeted protein degradation experiments directed toward SHP2 protein tyrosine phosphatase. The bifunctional molecule links a target-recognition element to cereblon, promoting proximity between the protein of interest and ubiquitination machinery. Productive ternary-complex formation can drive polyubiquitination and proteasome-dependent target depletion, allowing researchers to compare pharmacological inhibition with protein removal. It is suitable for evaluating degradation potency, kinetics, pathway selectivity, and downstream signaling consequences in engineered or disease-relevant cellular models.

Applications

• PROTAC-Mediated SHP2 Degradation: SHP2-D26 is utilized in research to achieve selective degradation of the SHP2 protein, a critical player in cell signaling pathways. By inducing targeted protein degradation, researchers can explore SHP2's role in oncogenesis and its potential as a therapeutic target in cancer biology.

• Targeted Protein Degradation Studies: Employing SHP2-D26 allows scientists to investigate the efficacy of PROTAC technology in degrading specific proteins. This application facilitates the study of protein function and the development of novel strategies for modulating protein levels in various cellular contexts.

• Signal Transduction Research: SHP2-D26 serves as a valuable tool in dissecting signal transduction pathways. By enabling precise protein degradation, researchers can delineate the contributions of SHP2 to cellular processes, enhancing our understanding of its involvement in diseases such as cancer and immune disorders.

1. Discovery of SHP2-D26 as a first, potent, and effective PROTAC degrader of SHP2 protein.

Wang, M., Lu, J., Wang, M., Yang, C.Y. and Wang, S., 2020. Journal of medicinal chemistry, 63(14), pp.7510-7528.

Src homology 2 domain-containing phosphatase 2 (SHP2) is an attractive therapeutic target for human cancers and other human diseases. Herein, we report our discovery of potent small-molecule SHP2 degraders whose design is based upon the proteolysis-targeting chimera (PROTAC) concept. This work has led to the discovery of potent and effective SHP2 degraders, exemplified by SHP2-D26. SHP2-D26 achieves DC50 values of 6.0 and 2.6 nM in esophageal cancer KYSE520 and acute myeloid leukemia MV4;11 cells, respectively, and is capable of reducing SHP2 protein levels by >95% in cancer cells. SHP2-D26 is >30-times more potent in inhibition of phosphorylation of extracellular signal-regulated kinase (ERK) and of cell growth than SHP099, a potent SHP2 inhibitor, in KYSE520 and MV4;11 cancer cell lines. This study demonstrates that induced SHP2 degradation is a very effective approach to inhibit the function of SHP2. Further optimization of these SHP2 degraders may lead to the development of a new class of therapies for cancers and other human diseases.

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