PLX647

dual inhibitor of FMS and KIT kinases CAS# 873786-09-5

PLX647

Catalog No. BCC6370----Order now to get a substantial discount!

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Chemical structure

PLX647

3D structure

Chemical Properties of PLX647

Cas No. 873786-09-5 SDF Download SDF
PubChem ID 11545419 Appearance Powder
Formula C21H17F3N4 M.Wt 382.38
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 25 mg/mL (65.38 mM; Need ultrasonic)
Chemical Name 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-[[4-(trifluoromethyl)phenyl]methyl]pyridin-2-amine
SMILES C1=CC2=C(NC=C2CC3=CN=C(C=C3)NCC4=CC=C(C=C4)C(F)(F)F)N=C1
Standard InChIKey NODCQQSEMCESEC-UHFFFAOYSA-N
Standard InChI InChI=1S/C21H17F3N4/c22-21(23,24)17-6-3-14(4-7-17)11-26-19-8-5-15(12-27-19)10-16-13-28-20-18(16)2-1-9-25-20/h1-9,12-13H,10-11H2,(H,25,28)(H,26,27)
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 PLX647

DescriptionPLX647 is a highly specific dual FMS/KIT kinase inhibitor with IC50 of 28/16 nM respectively. IC50 value: 28/16 nM(FMS/KIT) [1] Target: FMS/KIT dual inhibitor in vitro: PLX647 was tested against a panel of 400 kinases at a concentration of 1 μM, 35-fold above its FMS enzymatic IC50 and 60-fold above its KIT enzymatic IC50. In addition to FMS and KIT, the activities of only nine kinases were inhibited by more than 50%. PLX647 potently inhibits the growth of FLT3–ITD-expressing MV4-11 cells (IC50 = 0.11 μM) but not OCI-AML5 (IC50 = 1.6 μM), which express wild-type FLT3. PLX647 displayed minimal inhibition of the proliferation of Ba/F3 cells expressing BCR–KDR (IC50 = 5 μM) [1]. in vivo: PLX647 (40 mg/kg) was dosed orally 4.25 h before LPS injection. Treatment with PLX647 reduced serum TNF-α levels by 85% compared with the vehicle control. In the same experiment, the positive control dexamethasone (0.5 mg/kg, PO) lowered the TNF-α levels by 96%. Treatment with 40 mg/kg PLX647 also resulted in significant inhibition of IL-6 release (75%), with similar potency to dexamethasone (70%) . In the UUO kidneys, treatment with PLX647 [40 mg/kg twice daily (BID)] resulted in reduction in the levels of F4/80+ macrophages by 77% compared with vehicle [1].

References:
[1]. Zhang C, et al. Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor. Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5689-94. [2]. Louvet C, et al. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18895-900.

PLX647 Dilution Calculator

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Preparing Stock Solutions of PLX647

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.6152 mL 13.076 mL 26.152 mL 52.304 mL 65.38 mL
5 mM 0.523 mL 2.6152 mL 5.2304 mL 10.4608 mL 13.076 mL
10 mM 0.2615 mL 1.3076 mL 2.6152 mL 5.2304 mL 6.538 mL
50 mM 0.0523 mL 0.2615 mL 0.523 mL 1.0461 mL 1.3076 mL
100 mM 0.0262 mL 0.1308 mL 0.2615 mL 0.523 mL 0.6538 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.

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Background on PLX647

PLX647 is a potent and specific dual inhibitor of FMS and KIT kinases with IC50 values of 28 and 16 nM, respectively [1].

McDonough feline sarcoma viral (v-fms) oncogene homolog (FMS, also known as CSF1R) is a member of the platelet-derived growth factor receptor (PDGFR) family. Macrophage colony-stimulating factor (M-CSF or CSF-1) and interleukin 34 are two known FMS ligands. FMS plays important roles in regulating the survival, proliferation, and differentiation of monocyte/macrophage lineages. The stem cell factor (SCF) receptor v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) is also a member of the PDGFR family. Mutational activation of KIT occurs in many cancers [1].

PLX647 is a potent and specific dual inhibitor of FMS and KIT kinases. PLX647 showed aqueous solubility of 14 μM. PLX647 bound to the autoinhibited state of the KIT kinase with the juxtamembrane domain and prevented the activation loop from adopting the DFG-in conformation. In Ba/F3 cells expressing breakpoint cluster region activated kinase (BCR)-FMS and BCR-KIT, PLX647 inhibited cell proliferation with IC50 values of 0.092 and 0.18 μM. Also, PLX647 inhibited osteoclast differentiation with IC50 value of 0.17 μM [1].

In mice, PLX647 (40 mg/kg) significantly reduced LPS-induced TNF-α and IL-6 release by 85% and 75%, respectively. In an acute renal inflammation mouse model, PLX647 (40 mg/kg twice daily) reduced the levels of F4/80+ macrophages by 77% [1].

Reference:
[1].  Zhang C, Ibrahim PN, Zhang J, et al. Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor. Proc Natl Acad Sci U S A, 2013, 110(14): 5689-5694.

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References on PLX647

Colony-Stimulating Factor 1 Receptor Antagonists Sensitize Human Immunodeficiency Virus Type 1-Infected Macrophages to TRAIL-Mediated Killing.[Pubmed:27122585]

J Virol. 2016 Jun 24;90(14):6255-6262.

UNLABELLED: Strategies aimed at eliminating persistent viral reservoirs from HIV-1-infected individuals have focused on CD4(+) T-cell reservoirs. However, very little attention has been given to approaches that could promote elimination of tissue macrophage reservoirs. HIV-1 infection of macrophages induces phosphorylation of colony-stimulating factor 1 receptor (CSF-1R), which confers resistance to apoptotic pathways driven by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), thereby promoting viral persistence. In this study, we assessed whether CSF-1R antagonists (PLX647, PLX3397, and PLX5622) restored apoptotic sensitivity of HIV-1-infected macrophages in vitro PLX647, PLX3397, and PLX5622 at clinically relevant concentrations blocked the activation of CSF-1R and reduced the viability of infected macrophages, as well as the extent of viral replication. Our data show that strategies targeting monocyte colony-stimulating factor (MCSF) signaling could be used to promote elimination of HIV-1-infected myeloid cells and to contribute to the elimination of persistent viral reservoirs. IMPORTANCE: As the HIV/AIDS research field explores approaches to eliminate HIV-1 in individuals on suppressive antiviral therapy, those approaches will need to eliminate both CD4(+) T-cell and myeloid cell reservoirs. Most of the attention has focused on CD4(+) T-cell reservoirs, and scant attention has been paid to myeloid cell reservoirs. The distinct nature of the infection in myeloid cells versus CD4(+) T cells will likely dictate different approaches in order to achieve their elimination. For CD4(+) T cells, most strategies focus on promoting virus reactivation to promote immune-mediated clearance and/or elimination by viral cytopathicity. Macrophages resist viral cytopathic effects and CD8(+) T-cell killing. Therefore, we have explored clearance strategies that render macrophages sensitive to viral cytopathicity. This research helps inform the design of strategies to promote clearance of the macrophage reservoir in infected individuals on suppressive antiviral therapy.

Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice.[Pubmed:19015530]

Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18895-900.

The recent development of small-molecule tyrosine kinase (TK) inhibitors offers increasing opportunities for the treatment of autoimmune diseases. In this study, we investigated the potential of this new class of drugs to treat and cure type 1 diabetes (T1D) in the NOD mouse. Treatment of prediabetic and new onset diabetic mice with imatinib (Gleevec) prevented and reversed T1D. Similar results were observed with sunitinib (Sutent), an additional approved multikinase inhibitor, suggesting that the primary target of imatinib, c-Abl, was not essential in blocking disease in this model. Additional studies with another TK inhibitor, PLX647 (targeting c-Kit and c-Fms) or an anti-c-Kit mAb showed only marginal efficacy whereas a soluble form of platelet-derived growth factor receptor (PDGFR), PDGFRbetaIg, rapidly reversed diabetes. These findings strongly suggest that inhibition of PDGFR is critical to reverse diabetes and highlight a crucial role of inflammation in the development of T1D. These conclusions were supported by the finding that the adaptive immune system was not significantly affected by imatinib treatment. Finally, and most significantly, imatinib treatment led to durable remission after discontinuation of therapy at 10 weeks in a majority of mice. Thus, long-term efficacy and tolerance is likely to depend on inhibiting a combination of tyrosine kinases supporting the use of selective kinase inhibitors as a new, potentially very attractive approach for the treatment of T1D.

Description

PLX647 is a highly specific dual FMS/KIT kinase inhibitor with IC50 of 28/16 nM respectively.

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