WH-4-023

Lck/Src inhibitor,potent and selective CAS# 837422-57-8

WH-4-023

Catalog No. BCC8051----Order now to get a substantial discount!

Product Name & Size Price Stock
WH-4-023: 5mg $58 In Stock
WH-4-023: 10mg Please Inquire In Stock
WH-4-023: 20mg Please Inquire Please Inquire
WH-4-023: 50mg Please Inquire Please Inquire
WH-4-023: 100mg Please Inquire Please Inquire
WH-4-023: 200mg Please Inquire Please Inquire
WH-4-023: 500mg Please Inquire Please Inquire
WH-4-023: 1000mg Please Inquire Please Inquire
Related Products

Quality Control of WH-4-023

Number of papers citing our products

Chemical structure

WH-4-023

3D structure

Chemical Properties of WH-4-023

Cas No. 837422-57-8 SDF Download SDF
PubChem ID 11844351 Appearance Powder
Formula C32H36N6O4 M.Wt 568.67
Type of Compound N/A Storage Desiccate at -20°C
Synonyms KIN112
Solubility DMSO : ≥ 46.8 mg/mL (82.30 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name (2,6-dimethylphenyl) N-(2,4-dimethoxyphenyl)-N-[2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]carbamate
SMILES CC1=C(C(=CC=C1)C)OC(=O)N(C2=C(C=C(C=C2)OC)OC)C3=NC(=NC=C3)NC4=CC=C(C=C4)N5CCN(CC5)C
Standard InChIKey NBTNHSGBRGTFJS-UHFFFAOYSA-N
Standard InChI InChI=1S/C32H36N6O4/c1-22-7-6-8-23(2)30(22)42-32(39)38(27-14-13-26(40-4)21-28(27)41-5)29-15-16-33-31(35-29)34-24-9-11-25(12-10-24)37-19-17-36(3)18-20-37/h6-16,21H,17-20H2,1-5H3,(H,33,34,35)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of WH-4-023

DescriptionPotent and selective Lck and Src inhibitor (IC50 values are 2 and 6 nM respectively). Exhibits >300-fold selectivity against p38α and KDR. Also potently inhibits SIK (IC50 values are 10, 22 and 60 nM for SIK 1, 2 and 3 respectively) and displays selectivity over a range of closely related kinases. Supports self-renewal of naive hESCs in combination with PD 0325901, CHIR 99021 and SB 590885.

WH-4-023 Dilution Calculator

Concentration (start)
x
Volume (start)
=
Concentration (final)
x
Volume (final)
 
 
 
C1
V1
C2
V2

calculate

WH-4-023 Molarity Calculator

Mass
=
Concentration
x
Volume
x
MW*
 
 
 
g/mol

calculate

Preparing Stock Solutions of WH-4-023

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.7585 mL 8.7924 mL 17.5849 mL 35.1698 mL 43.9622 mL
5 mM 0.3517 mL 1.7585 mL 3.517 mL 7.034 mL 8.7924 mL
10 mM 0.1758 mL 0.8792 mL 1.7585 mL 3.517 mL 4.3962 mL
50 mM 0.0352 mL 0.1758 mL 0.3517 mL 0.7034 mL 0.8792 mL
100 mM 0.0176 mL 0.0879 mL 0.1758 mL 0.3517 mL 0.4396 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Organizitions Citing Our Products recently

 
 
 

Calcutta University

University of Minnesota

University of Maryland School of Medicine

University of Illinois at Chicago

The Ohio State University

University of Zurich

Harvard University

Colorado State University

Auburn University

Yale University

Worcester Polytechnic Institute

Washington State University

Stanford University

University of Leipzig

Universidade da Beira Interior

The Institute of Cancer Research

Heidelberg University

University of Amsterdam

University of Auckland
TsingHua University
TsingHua University
The University of Michigan
The University of Michigan
Miami University
Miami University
DRURY University
DRURY University
Jilin University
Jilin University
Fudan University
Fudan University
Wuhan University
Wuhan University
Sun Yat-sen University
Sun Yat-sen University
Universite de Paris
Universite de Paris
Deemed University
Deemed University
Auckland University
Auckland University
The University of Tokyo
The University of Tokyo
Korea University
Korea University

Background on WH-4-023

WH-4-023 is a potent and selective Lck and Src inhibitor with IC50 values of 2 and 6 nM, respectively [1]. It is also an inhibitor of IC50 values of 10, 22 and 60 nM for SIK 1, 2 and 3, respectively [2].

Lck and Src are cytoplasmic tyrosine kinases of the Src family expressed in T cells and NK cells [1]. SIKs restrict the formation of regulatory macrophages and that their inhibition greatly stimulates the production of IL-10 and other anti-inflammatory molecules [2].

WH-4-023 inhibited a number of protein tyrosine kinases that possess a Thr residue at the gatekeeper site, such as FGF and Ephrin receptors, Src family members (Src, Lck, and Yes) and BTK. WH-4-023 also inhibited the SIKs and did not inhibit any other member of the AMPK-related kinase subfamily, which all possess a large hydrophobic residue (Met or Leu) at the gatekeeper site. WH-4-023 inhibited SIK 1, 2 and 3 with IC50 values of 10, 22 and 60 nM, respectively. Also, WH-4-023 increased LPS-stimulated IL-10 production and greatly suppressed proinflammatory cytokine secretion [2].

References:
[1].  Martin MW, Newcomb J, Nunes JJ, et al. Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity. J Med Chem, 2006, 49(16): 4981-4991.
[2].  Clark K, MacKenzie KF, Petkevicius K, et al. Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages. Proc Natl Acad Sci U S A, 2012, 109(42): 16986-16991.

Featured Products
New Products
 

References on WH-4-023

Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia.[Pubmed:29101238]

Blood. 2017 Dec 21;130(25):2750-2761.

Pediatric T-acute lymphoblastic leukemia (T-ALL) patients often display resistance to glucocorticoid (GC) treatment. These patients, classified as prednisone poor responders (PPR), have poorer outcome than do the other pediatric T-ALL patients receiving a high-risk adapted therapy. Because glucocorticoids are administered to ALL patients during all the different phases of therapy, GC resistance represents an important challenge to improving the outcome for these patients. Mechanisms underlying resistance are not yet fully unraveled; thus our research focused on the identification of deregulated signaling pathways to point out new targeted approaches. We first identified, by reverse-phase protein arrays, the lymphocyte cell-specific protein-tyrosine kinase (LCK) as aberrantly activated in PPR patients. We showed that LCK inhibitors, such as dasatinib, bosutinib, nintedanib, and WH-4-023, are able to induce cell death in GC-resistant T-ALL cells, and remarkably, cotreatment with dexamethasone is able to reverse GC resistance, even at therapeutic drug concentrations. This was confirmed by specific LCK gene silencing and ex vivo combined treatment of cells from PPR patient-derived xenografts. Moreover, we observed that LCK hyperactivation in PPR patients upregulates the calcineurin/nuclear factor of activated T cells signaling triggering to interleukin-4 (IL-4) overexpression. GC-sensitive cells cultured with IL-4 display an increased resistance to dexamethasone, whereas the inhibition of IL-4 signaling could increase GC-induced apoptosis in resistant cells. Treatment with dexamethasone and dasatinib also impaired engraftment of leukemia cells in vivo. Our results suggest a quickly actionable approach to supporting conventional therapies and overcoming GC resistance in pediatric T-ALL patients.

Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages.[Pubmed:23033494]

Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16986-91.

Macrophages acquire strikingly different properties that enable them to play key roles during the initiation, propagation, and resolution of inflammation. Classically activated (M1) macrophages produce proinflammatory mediators to combat invading pathogens and respond to tissue damage in the host, whereas regulatory macrophages (M2b) produce high levels of anti-inflammatory molecules, such as IL-10, and low levels of proinflammatory cytokines, like IL-12, and are important for the resolution of inflammatory responses. A central problem in this area is to understand how the formation of regulatory macrophages can be promoted at sites of inflammation to prevent and/or alleviate chronic inflammatory and autoimmune diseases. Here, we demonstrate that the salt-inducible kinases (SIKs) restrict the formation of regulatory macrophages and that their inhibition induces striking increases in many of the characteristic markers of regulatory macrophages, greatly stimulating the production of IL-10 and other anti-inflammatory molecules. We show that SIK inhibitors elevate IL-10 production by inducing the dephosphorylation of cAMP response element-binding protein (CREB)-regulated transcriptional coactivator (CRTC) 3, its dissociation from 14-3-3 proteins and its translocation to the nucleus where it enhances a gene transcription program controlled by CREB. Importantly, the effects of SIK inhibitors on IL-10 production are lost in macrophages that express a drug-resistant mutant of SIK2. These findings identify SIKs as a key molecular switch whose inhibition reprograms macrophages to an anti-inflammatory phenotype. The remarkable effects of SIK inhibitors on macrophage function suggest that drugs that target these protein kinases may have therapeutic potential for the treatment of inflammatory and autoimmune diseases.

Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity.[Pubmed:16884310]

J Med Chem. 2006 Aug 10;49(16):4981-91.

The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-p yrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.

Description

WH-4-023 is a potent and selective dual Lck/Src inhibitor with IC50 of 2 nM/6 nM for Lck and Src kinase respectively; little inhibition on p38α and KDR.

Keywords:

WH-4-023,837422-57-8,KIN112,Natural Products,Src, buy WH-4-023 , WH-4-023 supplier , purchase WH-4-023 , WH-4-023 cost , WH-4-023 manufacturer , order WH-4-023 , high purity WH-4-023

Online Inquiry for:

      Fill out the information below

      • Size:Qty: - +

      * Required Fields

                                      Result: