CHIR99021

WNT pathway activator; Inhibits GSK3

CHIR99021

WNT pathway activator; Inhibits GSK3

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WNT pathway activator; Inhibits GSK3
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Overview

CHIR99021 is an aminopyrimidine derivative that is an extremely potent glycogen synthase kinase (GSK) 3 inhibitor, inhibiting both GSK3β (IC₅₀ = 6.7 nM) and GSK3α (IC₅₀ = 10 nM) (Ring et al.). GSK3 is a serine/threonine kinase that is a key inhibitor of the WNT pathway; therefore CHIR99021 functions as a WNT activator. It shows little activity against a large panel of kinases including CDK2 and other serine/threonine kinases such as MAPK and PKB (Bain et al.).

MAINTENANCE AND SELF-RENEWAL
· Maintains undifferentiated mouse ES cells in combination with PD0325901, in the absence of LIF (Ying et al.).
∙ Promotes self-renewal of human ES cells and mouse epiblast stem cells in combination with IWR-1 (Kim et al.).
∙ Allows derivation of ES cells from refractory mouse strains (Kiyonari et al., Ying et al.) and rat (Li P et al.) in combination with other small molecules.
· Maintains human and mouse hematopoietic stem cells in cytokine-free conditions, in combination with rapamycin (Huang et al.).
· Promotes growth of mouse and human intestinal stem cells (Wang et al.).

REPROGRAMMING
· Enables chemical reprogramming (without genetic factors) of mouse embryonic fibroblasts to iPS cells, in combination with Forskolin, Tranylcypromine, Valproic Acid, 3-Deazaneplanocin A, and E-616452 (Hou et al.).
∙ Promotes reprogramming of human somatic cells to iPS cells using OCT4, in combination with other small molecules (Zhu et al.).
∙ With OCT4, transdifferentiates human CD34+ hematopoietic cells to mesenchymal stem cells (Meng et al.).
· Direct lineage reprogramming of fibroblasts to mature neurons, in combination with Valproic Acid, RepSox, Forskolin, SP600125, Gö6983 and Y-27632 (Hu et al.).
· Direct lineage reprogramming of fibroblasts to mature neurons, in combination with Forskolin, ISX-9, SB431542, and I-BET151 (Li et al.).
· Generates mouse-like or “ground state” iPS cells from human and rat somatic cells, in combination with PD0325901 and A 83-01 (Li W et al. 2009).

DIFFERENTIATION
· Promotes differentiation of insulin-producing cells from human iPS cells (Kunisada et al.).
∙ Promotes differentiation of cardiomyocytes from human ES and iPS cells (Lian et al.).
∙ Generates and maintains primitive neural stem cells from human ES cells, in combination with SB431542 and Human Recombinant LIF (Li W et al. 2011).
Alternative Names
CT 99021
Cell Type
Cardiomyocytes, PSC-Derived, Endoderm, PSC-Derived, Hematopoietic Stem and Progenitor Cells, Mesoderm, PSC-Derived, Neural Cells, PSC-Derived, Neurons, Pancreatic Cells, Pluripotent Stem Cells
Species
Human, Mouse, Non-Human Primate, Other, Rat
Application
Differentiation, Expansion, Maintenance, Reprogramming
Area of Interest
Neuroscience, Stem Cell Biology
CAS Number
252917-06-9
Chemical Formula
C₂₂H₁₈Cl₂N₈
Molecular Weight
465.3 g/mol
Purity
≥ 95%
Pathway
WNT
Target
GSK3

Protocols and Documentation

Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.

Document Type
Product Name
Catalog #
Lot #
Language
Product Name
CHIR99021
Catalog #
100-1042, 72054, 72052
Lot #
All
Language
English
Document Type
Safety Data Sheet
Product Name
CHIR99021
Catalog #
100-1042
Lot #
All
Language
English
Document Type
Safety Data Sheet
Product Name
CHIR99021
Catalog #
72054, 72052
Lot #
All
Language
English

Resources and Publications

Publications (15)

Intrinsic Immunity Shapes Viral Resistance of Stem Cells. Wu X et al. Cell 2018 JAN

Abstract

Stem cells are highly resistant to viral infection compared to their differentiated progeny; however, the mechanism is mysterious. Here, we analyzed gene expression in mammalian stem cells and cells at various stages of differentiation. We find that, conserved across species, stem cells express a subset of genes previously classified as interferon (IFN) stimulated genes (ISGs) but that expression is intrinsic, as stem cells are refractory to interferon. This intrinsic ISG expression varies in a cell-type-specific manner, and many ISGs decrease upon differentiation, at which time cells become IFN responsive, allowing induction of a broad spectrum of ISGs by IFN signaling. Importantly, we show that intrinsically expressed ISGs protect stem cells against viral infection. We demonstrate the in vivo importance of intrinsic ISG expression for protecting stem cells and their differentiation potential during viral infection. These findings have intriguing implications for understanding stem cell biology and the evolution of pathogen resistance.
Direct Conversion of Normal and Alzheimer's Disease Human Fibroblasts into Neuronal Cells by Small Molecules. Hu W et al. Cell stem cell 2015 AUG

Abstract

Neuronal conversion from human fibroblasts can be induced by lineage-specific transcription factors; however, the introduction of ectopic genes limits the therapeutic applications of such induced neurons (iNs). Here, we report that human fibroblasts can be directly converted into neuronal cells by a chemical cocktail of seven small molecules, bypassing a neural progenitor stage. These human chemical-induced neuronal cells (hciNs) resembled hiPSC-derived neurons and human iNs (hiNs) with respect to morphology, gene expression profiles, and electrophysiological properties. This approach was further applied to generate hciNs from familial Alzheimer's disease patients. Taken together, our transgene-free and chemical-only approach for direct reprogramming of human fibroblasts into neurons provides an alternative strategy for modeling neurological diseases and for regenerative medicine.
Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons. Li X et al. Cell stem cell 2015 AUG

Abstract

Recently, direct reprogramming between divergent lineages has been achieved by the introduction of regulatory transcription factors. This approach may provide alternative cell resources for drug discovery and regenerative medicine, but applications could be limited by the genetic manipulation involved. Here, we show that mouse fibroblasts can be directly converted into neuronal cells using only a cocktail of small molecules, with a yield of up to textgreater90% being TUJ1-positive after 16 days of induction. After a further maturation stage, these chemically induced neurons (CiNs) possessed neuron-specific expression patterns, generated action potentials, and formed functional synapses. Mechanistically, we found that a BET family bromodomain inhibitor, I-BET151, disrupted the fibroblast-specific program, while the neurogenesis inducer ISX9 was necessary to activate neuron-specific genes. Overall, our findings provide a proof of principle" for chemically induced direct reprogramming of somatic cell fates across germ layers without genetic manipulation�