5054-59-1

Basic information

• Product Name: 4-Hydroxy ThalidoMide
• Synonyms: 4-Hydroxy ThalidoMide;2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione;2-(2,6-Dioxo-piperidin-3-yl)-4-hydroxy-isoindole-1,3-dione;2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-2,3-dihydro-1H-isoindole-1,3-dione;E3 ligase Ligand 2
• CAS NO: 5054-59-1
• Molecular Formula: C₁₃H₁₀N₂O₅
• Molecular Weight: 274.2289
• Mol File: 5054-59-1.mol

Chemical Properties

• Melting Point: 273-275 °C
• Boiling Point: 568.3±45.0 °C(Predicted)
• Appearance: /
• Density: 1.611±0.06 g/cm3(Predicted)
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• PKA: 6.82±0.20(Predicted)
• CAS DataBase Reference: 4-Hydroxy ThalidoMide(CAS DataBase Reference)
• NIST Chemistry Reference: 4-Hydroxy ThalidoMide(5054-59-1)
• EPA Substance Registry System: 4-Hydroxy ThalidoMide(5054-59-1)

Safety Data

• Hazardous Substances Data: 5054-59-1(Hazardous Substances Data)

Usage

Uses

Used in Cancer Research:
4-Hydroxy ThalidoMide is used as an intermediate for the synthesis of dTAG-13 (D710020), which is a degradation tag that has been tested for its efficiency at depleting FKBP12F36V-MELK(sg3R). It has been found to significantly degrade FKBP12F36V-MELK(sg3R) within 4 hours, making it a valuable tool in the study of cancer research.
Used in Drug Development:
4-Hydroxy ThalidoMide is used as a key component in the development of PROTACs, which are a promising new class of therapeutic agents that can modulate protein levels in cells. These agents have the potential to target a wide range of diseases, including cancer, by selectively degrading disease-causing proteins.
Used in Pharmaceutical Industry:
4-Hydroxy ThalidoMide is used as a starting material for the synthesis of various pharmaceutical compounds, including dTAG-13 (D710020). Its unique properties make it a valuable asset in the development of new drugs and therapies for a variety of medical conditions.
Used in Chemical Research:
4-Hydroxy ThalidoMide is used as a research compound in the field of chemical research, where it can be studied for its properties and potential applications in various chemical reactions and processes. Its unique structure and reactivity make it an interesting subject for further investigation and development.

Upstream product

• 27550-59-0 4-hydroxyphthalic anhydride 
• 24666-56-6 rac-α-aminoglutarimide hydrochloride 
• 37418-88-5 3-hydroxyphthalic anhydride 
• 2353-44-8 (+/-)-α-aminoglutarimide 

Downstream Products

• 2361493-16-3 N-(2-(2-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide 
• 1323404-18-7 2-(2,6-dioxopiperidin-3-yl)-4-((4-(morpholinomethyl)benzyl)oxy)isoindoline-1,3-dione 
• 1799711-25-3 N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide trifluoroacetate salt 

Relevant articles and documents

Preparation of targeted GSK3 alpha/beta degradation agent and medical application thereof

The invention discloses preparation of a targeted GSK3 alpha/beta degradation agent and a medical application thereof. The pharmaceutical composition comprises compounds or pharmaceutically acceptable salts thereof as shown in general formulas (I) and (II), R is selected from Cl and I, m is selected from 2, 3, 4, 5 and 6, and n is selected from 1, 2 and 4. The invention provides the degradation agent, and the compound disclosed by the invention can effectively degrade cell GSK3 alpha/beta in a targeting manner, and can be used as a therapeutic agent for Alzheimer's disease or other GSK3 protein related diseases.

Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation

Protein degradation is a promising strategy for drug development. Proteolysis-targeting chimeras (PROTACs) hijacking the E3 ligase cereblon (CRBN) exhibit enormous potential and universal degradation performance due to the small molecular weight of CRBN ligands. In this study, the CRBN-recruiting PROTACs were explored on the degradation of oncogenic fusion protein BCR-ABL, which drives the pathogenesis of chronic myeloid leukemia (CML). A series of novel PROTACs were synthesized by conjugating BCR-ABL inhibitor dasatinib to the CRBN ligand including pomalidomide and lenalidomide, and the extensive structure-activity relationship (SAR) studies were performed focusing on optimization of linker parameters. Therein, we uncovered that pomalidomide-based degrader 17 (SIAIS056), possessing sulfur-substituted carbon chain linker, exhibits the most potent degradative activity in vitro and favorable pharmacokinetics in vivo. Besides, degrader 17 also degrades a variety of clinically relevant resistance-conferring mutations of BCR-ABL. Furthermore, degrader 17 induces significant tumor regression against K562 xenograft tumors. Our study indicates that 17 as an efficacious BCR-ABL degrader warrants intensive investigation for the future treatment of BCR-ABL+ leukemia.

Proteolysis targeting chimera and application thereof

The invention provides a proteolysis targeting chimera and application thereof. According to a technical scheme in the invention, a novel PROTAC degradation agent compound 21a is developed on the basis of a BMS-37 small molecule. The novel PROTAC degradation agent compound 21a is an example of degrading membrane proteins on the basis of a ligand binding to the extracellular domain of a PD-L1 protein, and can effectively degrade PD-L1 in various malignant tumor cells. In-vivo research results show that after treatment with the compound 21a, the compound 21a can significantly reduce the level of the PD-L1 in tumors, promote infiltration of CD8T cells and significantly inhibit growth of mouse colorectal cancer MC-38 cells. The PROTAC molecule is expected to be one of novel and alternative strategies for cancer immunotherapy.

First orally bioavailable prodrug of proteolysis targeting chimera (PROTAC) degrades cyclin-dependent kinases 2/4/6 in vivo

A growing number of reports suggested that the inhibitor targeting cyclin-dependent kinases (CDK) 2/4/6 can act as a more feasible chemotherapy strategy. In the present paper, a novel PROTAC molecule was developed based on the structure of Ribociclib's derivative. In malignant melanoma cells, the degrader can not only degrade CDK 2/4/6 simultaneously and effectively, but also remarkably induce cell cycle arrest and apoptosis of melanoma cells. Moreover, PROTAC molecules with CRBN ligands always have poor oral bioavailability. We developed the orally bioavailable prodrug for the first time. It would provide general solution for oral administration of the PROTAC molecules, derived from CRBN ligands, for animal test conveniently.

In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC)

Immunotherapy via immune checkpoints blockade has aroused the attention of researchers worldwide. Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has been one of the most promising immunotherapy strategies. Several neutralizing antibodies targeting this interaction have been developed, which have already achieved considerable clinical success. Additionally, numerous pharmaceutical companies have been committed to develop small molecules which could block the interaction between PD-1 and PD-L1. In this study, a novel PROTAC molecule 21a was developed, and effectively induced the degradation of PD-L1 protein in various malignant cells in a proteasome-dependent manner. Moreover, compound 21a could significantly reduce PD-L1 protein levels of MC-38 cancer cells in vivo, by which promoted the invasion of CD8+ T cells and inhibited the growth of MC-38 in vivo. This PROTAC molecule could be used as a novel and alternative strategy for cancer immunotherapy.

Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2

EZH2 mediates both PRC2-dependent gene silencing via catalyzing H3K27me3 and PRC2-independent transcriptional activation in various cancers. Given its oncogenic role in cancers, EZH2 has constituted a compelling target for anticancer therapy. However, current EZH2 inhibitors only target its methyltransferase activity to downregulate H3K27me3 levels and show limited efficacy because of inadequate suppression of the EZH2 oncogenic activity. Therefore, therapeutic strategies to completely block the oncogenic activity of EZH2 are urgently needed. Herein, we report a series of EZH2-targeted proteolysis targeting chimeras (PROTACs) that induce proteasomal degradation of PRC2 components, including EZH2, EED, SUZ12, and RbAp48. Preliminary assessment identified E7 as the most active PROTAC molecule, which decreased PRC2 subunits and H3K27me2/3 levels in various cancer cells. Furthermore, E7 strongly inhibited transcriptional silencing mediated by EZH2 dependent on PRC2 and transcriptional activation mediated by EZH2 independent of PRC2, showing significant antiproliferative activities against cancer cell lines dependent on the enzymatic and nonenzymatic activities of EZH2.

Bifunctional compound capable of inducing PRC2 protein complex core subunit degradation, pharmaceutical composition and application

The invention discloses a bifunctional compound capable of inducing PRC2 protein complex core subunit degradation, a pharmaceutical composition and application. The bifunctional compound comprises a compound as shown in any one of formulas I-III, a pharmaceutically acceptable salt or prodrug thereof, a solvate thereof, a hydrate thereof, a polymorphic substance thereof, a tautomer thereof, a stereoisomer thereof or an isotope substituted compound thereof, wherein n in the formulas I-III is an integer from 1 to 10, X is O, N or S, and Y is O, H2 or S. The bifunctional compound can effectively induce degradation of a core subunit of a PRC2 protein complex, so that cancers mediated by the PRC2 complex and subunits thereof including EZH2, EED, SUZ12, RbAp46 and RbAp48 are treated, and the carcinogenic activity of the subunits of the PRC2 complex is completely blocked.

SMALL-MOLECULE INHIBITORS FOR THE Β-CATENIN/B-CELL LYMPHOMA 9 PROTEIN?PROTEIN INTERACTION

Disclosed are inhibitors for the β-catenin/B-cell lymphoma 9 interaction. The inhibitors are selective for β-catenin/B-cell lymphoma 9 over β-catenin/ E-cadherin PPI interaction. Methods of using the disclosed compounds to treat cancer are also disclosed.

Discovery of PT-65 as a highly potent and selective Proteolysis-targeting chimera degrader of GSK3 for treating Alzheimer's disease

GSK3 is a promising target for the treatment of Alzheimer's disease. Here, we describe the design and synthesize of a series of GSK3 degraders based on a click chemistry platform. A series of highly potent GSK3 degraders were obtained. Among them, PT-65 exhibited most potent degradation potency against GSK3α (DC50 = 28.3 nM) and GSK3β (DC50 = 34.2 nM) in SH-SY5Y cells. SPR assay confirmed that PT-65 binds to GSK3β with high affinity (KD = 12.41 nM). The proteomic study indicated that PT-65 could selectively induced GSK3 degradation. Moreover, PT-65 could effectively suppress GSK3β and Aβ mediated tau hyperphosphorylation in a dose-dependent manner and protect SH-SY5Y cells from Aβ caused cell damage. We also confirmed that PT-65 could suppress OA induced tau hyperphosphorylation and ameliorate learning and memory impairments in vivo model of AD. In summary, PT-65 might be a promising candidate for the treatment of AD.

Designed, synthesized and biological evaluation of proteolysis targeting chimeras (PROTACs) as AR degraders for prostate cancer treatment

As a continuation of our research on developing potent and potentially safe androgen receptor (AR) degrader, a series of novel proteolysis targeting chimeras (PROTACs) containing the phthalimide degrons with different linker were designed, synthesized and evaluated for their AR degradation activity against LNCaP (AR+) cell line. Most of the synthesized compounds displayed moderate to satisfactory AR binding affinity and might lead to antagonist activity against AR. Among them, compound A16 exhibited the best AR binding affinity (85%) and degradation activity against AR. Due to the strong fluorescence properties of pomalidomide derivatives, B10 was found to be effectively internalized and visualized in LNCaP (AR + ) cells than PC-3 (AR-) cells. Moreover, the molecular docking of A16 with AR and the active site of DDB1-CRBN E3 ubiquitin ligase complex provides guidance to design new PROTAC degrons targeting AR for prostate cancer therapy. These results represent a step toward the development of novel and improved AR PROTACs.