Name: PROTAC SGK3 degrader-1
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥95%

Solubility

Soluble in DMSO

Storage

Store at -20°C, stored under nitrogen

IUPACName

(2S,4R)-1-[(2S)-2-[[2-[2-[2-[6-[(2R)-2-[[6-[4-[(2-fluoro-5-methylphenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxymethyl]morpholin-4-yl]hexoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

Synonyms

(2S,4R)-1-((S)-2-(tert-butyl)-18-((R)-2-(((6-(4-((2-fluoro-5-methylphenyl)sulfonamido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)methyl)morpholino)-4-oxo-6,9,12-trioxa-3-azaoctadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; SGK3-PROTAC1; SGK3 degrader-1

Density

1.309±0.06 g/cm3

InChI Key

RTFQFPZKDYMMMJ-RIAKQDHQSA-N

InChI

InChI=1S/C57H73FN10O11S2/c1-37-10-19-46(58)48(28-37)81(73,74)66-42-17-15-41(16-18-42)52-63-53-45(31-61-65-53)55(64-52)79-34-44-33-67(21-23-78-44)20-8-6-7-9-22-75-24-25-76-26-27-77-35-49(70)62-51(57(3,4)5)56(72)68-32-43(69)29-47(68)54(71)59-30-39-11-13-40(14-12-39)50-38(2)60-36-80-50/h10-19,28,31,36,43-44,47,51,66,69H,6-9,20-27,29-30,32-35H2,1-5H3,(H,59,71)(H,62,70)(H,61,63,64,65)/t43-,44-,47+,51-/m1/s1

SMILES

O=C(NC(C(=O)N1CC(O)CC1C(=O)NCC=2C=CC(=CC2)C=3SC=NC3C)C(C)(C)C)COCCOCCOCCCCCCN4CCOC(COC5=NC(=NC=6NN=CC56)C=7C=CC(=CC7)NS(=O)(=O)C8=CC(=CC=C8F)C)C4

Mechanism

Target: Targets SGK3 serine/threonine kinase for experimental targeted protein degradation studies.

Binding Site: Binds the SGK3 ATP-binding kinase pocket and recruited E3 ligase ligand site to support productive ternary complex formation.

Mechanism of Action: PROTAC SGK3 degrader-1 is designed for use in PROTAC or targeted protein degradation experiments directed toward SGK3 serine/threonine kinase. 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

• SGK3 PROTAC-Mediated Degradation: This product facilitates the targeted degradation of serum/glucocorticoid-regulated kinase 3 (SGK3), enabling researchers to explore its role in cellular survival and proliferation. By selectively degrading SGK3, researchers can dissect its signaling pathways and potential as a therapeutic target in cancer biology.

• Functional Genomics with PROTAC: PROTAC SGK3 degrader-1 serves as a powerful tool in functional genomics studies, allowing scientists to perturb SGK3 activity and assess downstream effects. This targeted approach aids in elucidating gene function and interaction networks, advancing our understanding of cellular processes.

• Investigating Resistance Mechanisms: By employing this PROTAC, researchers can study mechanisms of resistance in cancer models where SGK3 plays a pivotal role. This application is crucial for identifying potential compensatory pathways and developing strategies to overcome therapeutic resistance.

• SGK3 Role in Metabolic Regulation: Utilizing PROTAC SGK3 degrader-1, researchers can analyze the kinase's involvement in metabolic pathways. This targeted degradation approach helps in understanding SGK3's contribution to metabolic disorders and its potential as a metabolic intervention target.

1. Design and characterization of SGK3-PROTAC1, an isoform specific SGK3 kinase PROTAC degrader.

Tovell, H., Testa, A., Zhou, H., Shpiro, N., Crafter, C., Ciulli, A. and Alessi, D.R., 2019. ACS chemical biology, 14(9), pp.2024-2034.

SGK3 is a PX domain containing protein kinase activated at endosomes downstream of class 1 and 3 PI3K family members by growth factors and oncogenic mutations. SGK3 plays a key role in mediating resistance of breast cancer cells to class 1 PI3K or Akt inhibitors, by substituting for the loss of Akt activity and restoring proliferative pathways such as mTORC1 signaling. It is therefore critical to develop tools to potently target SGK3 and obstruct its role in inhibitor resistance. Here, we describe the development of SGK3-PROTAC1, a PROTAC conjugate of the 308-R SGK inhibitor with the VH032 VHL binding ligand, targeting SGK3 for degradation. SGK3-PROTAC1 (0.3 μM) induced 50% degradation of endogenous SGK3 within 2 h, with maximal 80% degradation observed within 8 h, accompanied by a loss of phosphorylation of NDRG1, an SGK3 substrate. SGK3-PROTAC1 did not degrade closely related SGK1 and SGK2 isoforms that are nevertheless engaged and inhibited by 308-R. Proteomic analysis revealed that SGK3 was the only cellular protein whose cellular levels were significantly reduced following treatment with SGK3-PROTAC1. Low doses of SGK3-PROTAC1 (0.1-0.3 μM) restored sensitivity of SGK3 dependent ZR-75-1 and CAMA-1 breast cancer cells to Akt (AZD5363) and PI3K (GDC0941) inhibitors, whereas the cis epimer analogue incapable of binding to the VHL E3 ligase had no impact. SGK3-PROTAC1 suppressed proliferation of ZR-75-1 and CAMA-1 cancer cell lines treated with a PI3K inhibitor (GDC0941) more effectively than could be achieved by a conventional SGK isoform inhibitor (14H). This work underscores the benefit of the PROTAC approach in targeting protein kinase signaling pathways with greater efficacy and selectivity than can be achieved with conventional inhibitors. SGK3-PROTAC1 will be an important reagent to explore the roles of the SGK3 pathway.

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