CHIR-99021
[CAS# 252917-06-9]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyridine compound >> Ethylpyridine
• Name: CHIR-99021
• Synonyms: GSK-3 Inhibitor XVI; 6-[2-[4-(2,4-Dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)pyrimidin-2-ylamino]ethylamino]pyridine-3-carbonitrile
• Molecular Formula: C₂₂H₁₈Cl₂N₈
• Molecular Weight: 465.34
• CAS Registry Number: 252917-06-9
• EC Number: 809-015-4
• SMILES: CC1=CN=C(N1)C2=CN=C(N=C2C3=C(C=C(C=C3)Cl)Cl)NCCNC4=NC=C(C=C4)C#N

Properties

• Density: 1.5±0.1 g/cm³ Calc.^*
• Boiling point: 784.1±70.0 °C 760 mmHg (Calc.)^*
• Flash point: 428.0±35.7 °C (Calc.)^*
• Solubility: Soluble 20 mM (DMSO) (Expl.)
• Index of refraction: 1.7 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS06;GHS07 Danger
• Risk Statements: H300-H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P270-P271-P280-P301+P316-P302+P352-P304+P340-P305+P351+P338-P319-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute toxicity	Acute Tox.	2	H300
Acute toxicity	Acute Tox.	3	H301
Acute toxicity	Acute Tox.	3	H331
Acute toxicity	Acute Tox.	4	H332
Acute toxicity	Acute Tox.	3	H311
Acute toxicity	Acute Tox.	4	H312
Acute toxicity	Acute Tox.	4	H302

Discovery and Applications

CHIR-99021 is a small molecule that acts as a potent and selective inhibitor of glycogen synthase kinase-3 (GSK-3). GSK-3 is a serine/threonine kinase involved in a variety of cellular processes, including metabolism, cell cycle regulation, and gene expression. It plays a significant role in the regulation of insulin signaling, neuronal development, and inflammation. Due to its involvement in these processes, GSK-3 has been implicated in a number of diseases, including diabetes, Alzheimer's disease, and certain cancers.

The discovery of CHIR-99021 arose from the need to develop a selective and effective GSK-3 inhibitor for research purposes and potential therapeutic applications. Unlike earlier GSK-3 inhibitors, which often lacked specificity or had undesirable off-target effects, CHIR-99021 is known for its high selectivity and potent inhibition of GSK-3 activity. This selectivity allows researchers to investigate the specific role of GSK-3 in various biological processes and its potential as a therapeutic target.

CHIR-99021 works by binding to the ATP-binding pocket of GSK-3, inhibiting its kinase activity. This inhibition disrupts the normal phosphorylation processes regulated by GSK-3, which can lead to changes in cellular signaling pathways. In particular, inhibition of GSK-3 by CHIR-99021 has been shown to modulate several key biological processes, including the regulation of beta-catenin, a protein involved in the Wnt signaling pathway. The Wnt pathway plays a critical role in cell proliferation, differentiation, and survival, making it a crucial target in cancer research and regenerative medicine.

The applications of CHIR-99021 are broad, particularly in the fields of stem cell research, neuroscience, and cancer therapy. In stem cell biology, CHIR-99021 is widely used to activate the Wnt/β-catenin signaling pathway, which is important for the maintenance and self-renewal of pluripotent stem cells. By inhibiting GSK-3, CHIR-99021 enhances the stabilization of β-catenin, promoting the activation of target genes involved in stem cell pluripotency and differentiation. As a result, CHIR-99021 has become an essential tool in the study of stem cell biology and the development of induced pluripotent stem cells (iPSCs).

In neuroscience, CHIR-99021 has been investigated for its potential to promote neurogenesis and repair damaged neural tissue. GSK-3 inhibition has been shown to support the survival and differentiation of neural progenitor cells, making CHIR-99021 a candidate for therapies aimed at treating neurodegenerative diseases, such as Alzheimer's disease. The drug's ability to modulate the activity of GSK-3 in the central nervous system may help counteract the neurotoxic effects associated with the hyperactivity of GSK-3 in conditions like Alzheimer's disease.

In cancer research, CHIR-99021's inhibition of GSK-3 has shown promise in regulating the growth of cancer cells. GSK-3 is involved in regulating key signaling pathways that control cell survival, apoptosis, and proliferation. By inhibiting GSK-3, CHIR-99021 can interfere with cancer cell proliferation and promote cell death, particularly in cancers where GSK-3 is overactive or dysregulated. Ongoing studies are exploring the potential of CHIR-99021 as an adjuvant therapy in combination with other cancer treatments.

While CHIR-99021 has shown significant potential in various research applications, it is important to note that its use in clinical settings is still in the early stages. The compound is mainly used in laboratory studies to investigate the role of GSK-3 in disease and cellular processes. As with any potent kinase inhibitor, the long-term effects and potential side effects of GSK-3 inhibition remain areas of active investigation.

In conclusion, CHIR-99021 is a valuable tool in biomedical research due to its ability to selectively inhibit GSK-3, a kinase involved in many important cellular pathways. Its applications in stem cell biology, neuroscience, and cancer research have shown promising results, making it a compound of interest for potential therapeutic development. However, further studies are required to fully understand its long-term effects and therapeutic potential in clinical settings.

References

2003. Selective Glycogen Synthase Kinase 3 Inhibitors Potentiate Insulin Activation of Glucose Transport and Utilization In Vitro and In Vivo. Diabetes, 52(3).
DOI: 10.2337/diabetes.52.3.588

2023. The regenerative potential of Tideglusib and CHIR99021 small molecules as potent odontogenic differentiation enhancers of human dental pulp stem cells. Clinical Oral Investigations, 28(1).
DOI: 10.1007/s00784-023-05452-x

2024. Generation of human hepatobiliary organoids with a functional bile duct from chemically induced liver progenitor cells. Stem Cell Research & Therapy, 15(1).
DOI: 10.1186/s13287-024-03877-z