WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 206178
CAS#: 1029044-16-3 (free base)
Description: Pexidartinib, also know as PLX-3397, is a CSF1R inhibitor with IC50 of 20 nM in development by Plexxikon for the treatment of tenosynovial giant cell tumors. It is in a phase 3 clinical trial for Pigmented Villonodular Synovitis (PVNS) or Giant Cell Tumor of the Tendon Sheath (GCT-TS).
MedKoo Cat#: 206178
Name: Pexidartinib (PLX3397)
CAS#: 1029044-16-3 (free base)
Chemical Formula: C20H15ClF3N5
Exact Mass: 417.09681
Molecular Weight: 417.81
Elemental Analysis: C, 57.49; H, 3.62; Cl, 8.49; F, 13.64; N, 16.76
Synonym: PLX3397; PLX-3397; PLX 3397; CML-261; CML 261; CML261; FP-113; FP 113; FP113; Pexidartinib; Turalio
IUPAC/Chemical Name: 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine
InChi Key: JGWRKYUXBBNENE-UHFFFAOYSA-N
InChi Code: InChI=1S/C20H15ClF3N5/c21-15-6-16-14(10-28-19(16)29-11-15)5-12-2-4-18(26-7-12)27-9-13-1-3-17(25-8-13)20(22,23)24/h1-4,6-8,10-11H,5,9H2,(H,26,27)(H,28,29)
SMILES Code: FC(C1=CC=C(CNC2=NC=C(CC3=CNC4=NC=C(Cl)C=C43)C=C2)C=N1)(F)F
Appearance: Yellow solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO (20mg/ mL), not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
|Biological target:||ATP-competitive CSF1R and c-Kit inhibitor, with IC50s of 20 and 10 nM|
|In vitro activity:||Having established the expression and activation of CSF1R in TCL, a loss-of-function strategy was adopted to address its potential oncogenic role in these TCL using complementary molecular and pharmacologic approaches. The first compound used was a clinically available and rationally designed tyrosine kinase inhibitor that is selective for CSF1R (Pexidartinib, PLX3397). In order to confirm CSF1R inhibition upon pexidartinib treatment, TCL cells with autocrine-activation of CSF1R were treated with pexidartinib. A marked decrease in CSF1R phosphorylation was observed upon treatment with pexidartinib (Figure 2A, supplementary figure 4A). Importantly, pexidartinib did not show any effect on the phosphorylation levels of the oncogenic kinase NPM-ALK which is expressed in a portion of the TCL cells evaluated (supplementary figure 4B). In addition, a dose-dependent decrease in proliferation was observed with exposure to pexidartinib (Figure 2B and supplementary figure 4D–E), however these effects were not observed in TCL cells that do not express CSF1R, supporting the relative selectivity of this FDA-approved agent (supplementary figure 4C). Consistent with these findings, treatment with pexidartinib was associated with increased apoptosis of TCL cells, as demonstrated by phosphatidylserine exposure (Figure 2C–E), PARP cleavage and Caspase 3 cleavage (Figure 2F and supplementary figure 4F). Reference: Clin Cancer Res. 2020 Feb 1; 26(3): 690–703. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002219/|
|In vivo activity:||To determine if treatment with the CSF1R inhibitor pexidartinib (PEX) depletes macrophages, PEX was administered via chow fed to GfapR236H/+ AxD model mice for a period of 2.5 months, beginning at weaning. Previous reports indicate that PEX treatment can raise GFAP levels in wild-type mice; therefore, wild-type (WT, Gfap+/+) littermates were also fed PEX or control chow as a comparison. The numbers of macrophages (IBA1+ cells) were counted in the olfactory bulb glomerular layer and the dentate gyrus of the hippocampus, areas that have been observed to display Rosenthal fibers in histological analyses. As expected, significant increases in the number of IBA1+ cells were observed in both regions in AxD compared to WT animals fed control chow (Fig.2a and b, representative images: Additional figure 1a and b). PEX treatment of AxD mice resulted in depletion of macrophages in both brain regions (Fig.2a and b). PEX treatment in WT mice did reduce macrophage numbers in the dentate gyrus, but not in a statistically significant manner in the olfactory bulb glomerular layer (Fig.2a and b). RT-qPCR for Aif1 (the gene encoding IBA1) revealed a similar decrease in PEX-treated mice (Fig.2c and d). Together, these data indicate that PEX treatment reduces brain macrophage numbers in AxD mice and may have region specific effects in WT mice. Reference: J Neuroinflammation. 2021; 18: 67. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941726/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
|DMF:PBS (pH 7.2) (1:3)||0.25||0.6|
The following data is based on the product molecular weight 417.81 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|Formulation protocol:||1. Murga-Zamalloa C, Rolland DCM, Polk A, Wolfe A, Dewar H, Chowdhury P, Onder O, Dewar R, Brown NA, Bailey NG, Inamdar K, Lim MS, Elenitoba-Johnson KSJ, Wilcox RA. Colony-Stimulating Factor 1 Receptor (CSF1R) Activates AKT/mTOR Signaling and Promotes T-Cell Lymphoma Viability. Clin Cancer Res. 2020 Feb 1;26(3):690-703. doi: 10.1158/1078-0432.CCR-19-1486. Epub 2019 Oct 21. PMID: 31636099; PMCID: PMC7002219. 2. Liu Y, Given KS, Dickson EL, Owens GP, Macklin WB, Bennett JL. Concentration-dependent effects of CSF1R inhibitors on oligodendrocyte progenitor cells ex vivo and in vivo. Exp Neurol. 2019 Aug;318:32-41. doi: 10.1016/j.expneurol.2019.04.011. Epub 2019 Apr 25. PMID: 31029597; PMCID: PMC6615458. 3. Boyd MM, Litscher SJ, Seitz LL, Messing A, Hagemann TL, Collier LS. Pexidartinib treatment in Alexander disease model mice reduces macrophage numbers and increases glial fibrillary acidic protein levels, yet has minimal impact on other disease phenotypes. J Neuroinflammation. 2021 Mar 8;18(1):67. doi: 10.1186/s12974-021-02118-x. PMID: 33685480; PMCID: PMC7941726.|
|In vitro protocol:||1. Murga-Zamalloa C, Rolland DCM, Polk A, Wolfe A, Dewar H, Chowdhury P, Onder O, Dewar R, Brown NA, Bailey NG, Inamdar K, Lim MS, Elenitoba-Johnson KSJ, Wilcox RA. Colony-Stimulating Factor 1 Receptor (CSF1R) Activates AKT/mTOR Signaling and Promotes T-Cell Lymphoma Viability. Clin Cancer Res. 2020 Feb 1;26(3):690-703. doi: 10.1158/1078-0432.CCR-19-1486. Epub 2019 Oct 21. PMID: 31636099; PMCID: PMC7002219. 2. Liu Y, Given KS, Dickson EL, Owens GP, Macklin WB, Bennett JL. Concentration-dependent effects of CSF1R inhibitors on oligodendrocyte progenitor cells ex vivo and in vivo. Exp Neurol. 2019 Aug;318:32-41. doi: 10.1016/j.expneurol.2019.04.011. Epub 2019 Apr 25. PMID: 31029597; PMCID: PMC6615458.|
|In vivo protocol:||1. Boyd MM, Litscher SJ, Seitz LL, Messing A, Hagemann TL, Collier LS. Pexidartinib treatment in Alexander disease model mice reduces macrophage numbers and increases glial fibrillary acidic protein levels, yet has minimal impact on other disease phenotypes. J Neuroinflammation. 2021 Mar 8;18(1):67. doi: 10.1186/s12974-021-02118-x. PMID: 33685480; PMCID: PMC7941726.|
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Pexidartinib (PLX3397) is a small-molecule receptor tyrosine kinase (RTK) inhibitor of KIT, CSF1R and FLT3 with potential antineoplastic activity. Pexidartinib binds to and inhibits phosphorylation of stem cell factor receptor (KIT), colony-stimulating factor-1 receptor (CSF1R) and FMS-like tyrosine kinase 3 (FLT3), which may result in the inhibition of tumor cell proliferation and down-modulation of macrophages, osteoclasts and mast cells involved in the osteolytic metastatic disease. FLT3, CSF1R and FLT3 are overexpressed or mutated in many cancer cell types and play major roles in tumor cell proliferation and metastasis.