Pexidartinib (PLX3397)
featured

    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).


Chemical Structure

img
Pexidartinib (PLX3397)
CAS# 1029044-16-3 (free base)

Theoretical Analysis

MedKoo Cat#: 206178
Name: Pexidartinib (PLX3397)
CAS#: 1029044-16-3 (free base)
Chemical Formula: C20H15ClF3N5
Exact Mass: 417.10
Molecular Weight: 417.810
Elemental Analysis: C, 57.49; H, 3.62; Cl, 8.49; F, 13.64; N, 16.76

Price and Availability

Size Price Availability Quantity
100mg USD 150 Ready to ship
200mg USD 225 Ready to ship
500mg USD 450 Ready to ship
1g USD 750 Ready to ship
2g USD 1250 Ready to ship
5g USD 2850 Ready to ship
10g USD 4850 Ready to Ship
Bulk inquiry

Related CAS #: 1029044-16-3 (free base)   2040295-03-0 (HCl)   2169310-71-6 (2HCl)    

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

More Info: 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.      

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/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMF 20.0 47.87
DMF:PBS (pH 7.2) (1:3) 0.3 0.60
DMSO 42.7 102.13

Preparing Stock Solutions

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.

Recalculate based on batch purity %
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.

Molarity Calculator

Calculate the mass, volume, or concentration required for a solution.
=
x
x
g/mol

*When preparing stock solutions always use the batch-specific molecular weight of the product found on the vial label and SDS / CoA (available online).

Reconstitution Calculator

The reconstitution calculator allows you to quickly calculate the volume of a reagent to reconstitute your vial. Simply enter the mass of reagent and the target concentration and the calculator will determine the rest.

=
÷

Dilution Calculator

Calculate the dilution required to prepare a stock solution.
x
=
x

1: Murga-Zamalloa C, Rolland DC, Polk A, Wolfe A, Dewar H, Chowdhury P, Önder Ö, 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. 2019 Oct 21. pii: clincanres.1486.2019. doi: 10.1158/1078-0432.CCR-19-1486. [Epub ahead of print] PubMed PMID: 31636099.

2: Lamb YN. Pexidartinib: First Approval. Drugs. 2019 Nov;79(16):1805-1812. doi: 10.1007/s40265-019-01210-0. Review. PubMed PMID: 31602563.

3: Mason C, Kossatz S, Carter L, Pirovano G, Brand C, Guru N, Pérez-Medina C, Lewis JS, Mulder W, Reiner T. A (89)Zr-HDL PET tracer monitors response to a CSF1R inhibitor. J Nucl Med. 2019 Aug 16. pii: jnumed.119.230466. doi: 10.2967/jnumed.119.230466. [Epub ahead of print] PubMed PMID: 31420495.

4: Wesolowski R, Sharma N, Reebel L, Rodal MB, Peck A, West BL, Marimuthu A, Severson P, Karlin DA, Dowlati A, Le MH, Coussens LM, Rugo HS. Phase Ib study of the combination of pexidartinib (PLX3397), a CSF-1R inhibitor, and paclitaxel in patients with advanced solid tumors. Ther Adv Med Oncol. 2019 Jun 21;11:1758835919854238. doi: 10.1177/1758835919854238. eCollection 2019. PubMed PMID: 31258629; PubMed Central PMCID: PMC6589951.

5: Piawah S, Hyland C, Umetsu SE, Esserman LJ, Rugo HS, Chien AJ. A case report of vanishing bile duct syndrome after exposure to pexidartinib (PLX3397) and paclitaxel. NPJ Breast Cancer. 2019 Jun 14;5:17. doi: 10.1038/s41523-019-0112-z. eCollection 2019. PubMed PMID: 31240240; PubMed Central PMCID: PMC6570645.

6: Tap WD, Gelderblom H, Palmerini E, Desai J, Bauer S, Blay JY, Alcindor T, Ganjoo K, Martín-Broto J, Ryan CW, Thomas DM, Peterfy C, Healey JH, van de Sande M, Gelhorn HL, Shuster DE, Wang Q, Yver A, Hsu HH, Lin PS, Tong-Starksen S, Stacchiotti S, Wagner AJ; ENLIVEN investigators. Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. Lancet. 2019 Aug 10;394(10197):478-487. doi: 10.1016/S0140-6736(19)30764-0. Epub 2019 Jun 19. PubMed PMID: 31229240; PubMed Central PMCID: PMC6860022.

7: Eissmann MF, Dijkstra C, Jarnicki A, Phesse T, Brunnberg J, Poh AR, Etemadi N, Tsantikos E, Thiem S, Huntington ND, Hibbs ML, Boussioutas A, Grimbaldeston MA, Buchert M, O'Donoghue RJJ, Masson F, Ernst M. IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nat Commun. 2019 Jun 21;10(1):2735. doi: 10.1038/s41467-019-10676-1. PubMed PMID: 31227713; PubMed Central PMCID: PMC6588585.

8: Rosenbaum E, Kelly C, D'Angelo SP, Dickson MA, Gounder M, Keohan ML, Movva S, Condy M, Adamson T, Mcfadyen CR, Antonescu CR, Hwang S, Singer S, Qin LX, Tap WD, Chi P. A Phase I Study of Binimetinib (MEK162) Combined with Pexidartinib (PLX3397) in Patients with Advanced Gastrointestinal Stromal Tumor. Oncologist. 2019 Oct;24(10):1309-e983. doi: 10.1634/theoncologist.2019-0418. Epub 2019 Jun 18. PubMed PMID: 31213500; PubMed Central PMCID: PMC6795162.

9: Li X, Jue L, Wang S, Pang X. [Pexidartinib inhibits the aggregation of monocytes into tumor microenvironment and reduces the number of M2 tumor-associated macrophages]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2019 Apr;35(4):307-312. Chinese. PubMed PMID: 31167689.

10: Miladinovic T, Sharma M, Phan A, Geres H, Ungard RG, Linher-Melville K, Singh G. Activation of hippocampal microglia in a murine model of cancer-induced pain. J Pain Res. 2019 Mar 18;12:1003-1016. doi: 10.2147/JPR.S191860. eCollection 2019. PubMed PMID: 30936739; PubMed Central PMCID: PMC6430067.

11: Merry TL, Brooks AES, Masson SW, Adams SE, Jaiswal JK, Jamieson SMF, Shepherd PR. The CSF1 receptor inhibitor pexidartinib (PLX3397) reduces tissue macrophage levels without affecting glucose homeostasis in mice. Int J Obes (Lond). 2019 Mar 29. doi: 10.1038/s41366-019-0355-7. [Epub ahead of print] PubMed PMID: 30926949.

12: Zhu Y, Yang J, Xu D, Gao XM, Zhang Z, Hsu JL, Li CW, Lim SO, Sheng YY, Zhang Y, Li JH, Luo Q, Zheng Y, Zhao Y, Lu L, Jia HL, Hung MC, Dong QZ, Qin LX. Disruption of tumour-associated macrophage trafficking by the osteopontin-induced colony-stimulating factor-1 signalling sensitises hepatocellular carcinoma to anti-PD-L1 blockade. Gut. 2019 Sep;68(9):1653-1666. doi: 10.1136/gutjnl-2019-318419. Epub 2019 Mar 22. PubMed PMID: 30902885.

13: Pang L, Pei Y, Uzunalli G, Hyun H, Lyle LT, Yeo Y. Surface Modification of Polymeric Nanoparticles with M2pep Peptide for Drug Delivery to Tumor-Associated Macrophages. Pharm Res. 2019 Mar 11;36(4):65. doi: 10.1007/s11095-019-2596-5. PubMed PMID: 30859335; PubMed Central PMCID: PMC6622458.

14: Lee JH, Chen TW, Hsu CH, Yen YH, Yang JC, Cheng AL, Sasaki SI, Chiu LL, Sugihara M, Ishizuka T, Oguma T, Tajima N, Lin CC. A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors. Invest New Drugs. 2019 Mar 2. doi: 10.1007/s10637-019-00745-z. [Epub ahead of print] PubMed PMID: 30825104.

15: Kurelac I, Iommarini L, Vatrinet R, Amato LB, De Luise M, Leone G, Girolimetti G, Umesh Ganesh N, Bridgeman VL, Ombrato L, Columbaro M, Ragazzi M, Gibellini L, Sollazzo M, Feichtinger RG, Vidali S, Baldassarre M, Foriel S, Vidone M, Cossarizza A, Grifoni D, Kofler B, Malanchi I, Porcelli AM, Gasparre G. Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses. Nat Commun. 2019 Feb 22;10(1):903. doi: 10.1038/s41467-019-08839-1. PubMed PMID: 30796225; PubMed Central PMCID: PMC6385215.

16: Qiao S, Qian Y, Xu G, Luo Q, Zhang Z. Long-term characterization of activated microglia/macrophages facilitating the development of experimental brain metastasis through intravital microscopic imaging. J Neuroinflammation. 2019 Jan 7;16(1):4. doi: 10.1186/s12974-018-1389-9. PubMed PMID: 30616691; PubMed Central PMCID: PMC6323850.

17: Groh J, Klein D, Berve K, West BL, Martini R. Targeting microglia attenuates neuroinflammation-related neural damage in mice carrying human PLP1 mutations. Glia. 2019 Feb;67(2):277-290. doi: 10.1002/glia.23539. Epub 2018 Nov 22. PubMed PMID: 30565754.

18: Shi G, Yang Q, Zhang Y, Jiang Q, Lin Y, Yang S, Wang H, Cheng L, Zhang X, Li Y, Wang Q, Liu Y, Wang Q, Zhang H, Su X, Dai L, Liu L, Zhang S, Li J, Li Z, Yang Y, Yu D, Wei Y, Deng H. Modulating the Tumor Microenvironment via Oncolytic Viruses and CSF-1R Inhibition Synergistically Enhances Anti-PD-1 Immunotherapy. Mol Ther. 2019 Jan 2;27(1):244-260. doi: 10.1016/j.ymthe.2018.11.010. Epub 2018 Nov 17. PubMed PMID: 30527756; PubMed Central PMCID: PMC6319306.

19: Bennett RE, Bryant A, Hu M, Robbins AB, Hopp SC, Hyman BT. Partial reduction of microglia does not affect tau pathology in aged mice. J Neuroinflammation. 2018 Nov 9;15(1):311. doi: 10.1186/s12974-018-1348-5. PubMed PMID: 30413160; PubMed Central PMCID: PMC6230271.

20: Takeda A, Shinozaki Y, Kashiwagi K, Ohno N, Eto K, Wake H, Nabekura J, Koizumi S. Microglia mediate non-cell-autonomous cell death of retinal ganglion cells. Glia. 2018 Nov;66(11):2366-2384. doi: 10.1002/glia.23475. Epub 2018 Oct 29. PubMed PMID: 30375063.

1. De Sousa VL, Araújo SB, Antonio LM, Silva-Queiroz M, Colodeti LC, Soares C, Barros-Aragão F, Mota-Araujo HP, Alves VS, Coutinho-Silva R, Savio LEB, Ferreira ST, Da Costa R, Clarke JR, Figueiredo CP. Innate immune memory mediates increased susceptibility to Alzheimer's disease-like pathology in sepsis surviving mice. Brain Behav Immun. 2021 Apr 8:S0889-1591(21)00158-6. doi: 10.1016/j.bbi.2021.04.001. Epub ahead of print. PMID: 33838250.

2. Luo F, Li H, Ma W, Cao J, Chen Q, Lu F, Qiu M, Zhou P, Xia Z, Zeng K, Zhan J, Zhou T, Luo Q, Pan W, Zhang L, Lin C, Huang Y, Zhang L, Yang D, Zhao H. The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation. Cell Mol Immunol. 2024 Jan;21(1):60-79. doi: 10.1038/s41423-023-01112-y. Epub 2023 Dec 7. PMID: 38062129; PMCID: PMC10757718.

3. Damisah EC, Hill RA, Rai A, Chen F, Rothlin CV, Ghosh S, Grutzendler J. Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo. Sci Adv. 2020 Jun 26;6(26):eaba3239. doi: 10.1126/sciadv.aba3239. PMID: 32637606; PMCID: PMC7319765.

4. Son Y, Jeong YJ, Shin NR, Oh SJ, Nam KR, Choi HD, Choi JY, Lee HJ. Inhibition of Colony-Stimulating Factor 1 Receptor by PLX3397 Prevents Amyloid Beta Pathology and Rescues Dopaminergic Signaling in Aging 5xFAD Mice. Int J Mol Sci. 2020 Aug 3;21(15):5553. doi: 10.3390/ijms21155553. PMID: 32756440; PMCID: PMC7432084.

5. Son Y, Park HJ, Jeong YJ, Choi HD, Kim N, Lee HJ. Long-term radiofrequency electromagnetic fields exposure attenuates cognitive dysfunction in 5×FAD mice by regulating microglial function. Neural Regen Res. 2023 Nov;18(11):2497-2503. doi: 10.4103/1673-5374.371379. PMID: 37282482; PMCID: PMC10360091.

6. Rao R, Han R, Ogurek S, Xue C, Wu LM, Zhang L, Zhang L, Hu J, Phoenix TN, Waggoner SN, Lu QR. Glioblastoma genetic drivers dictate the function of tumor-associated macrophages/microglia and responses to CSF1R inhibition. Neuro Oncol. 2022 Apr 1;24(4):584-597. doi: 10.1093/neuonc/noab228. PMID: 34562087; PMCID: PMC8972285.

7. Lim C, Hwang D, Yazdimamaghani M, Atkins HM, Hyun H, Shin Y, Ramsey JD, Rädler PD, Mott KR, Perou CM, Sokolsky-Papkov M, Kabanov AV. High-Dose Paclitaxel and its Combination with CSF1R Inhibitor in Polymeric Micelles for Chemoimmunotherapy of Triple Negative Breast Cancer. Nano Today. 2023 Aug;51:101884. doi: 10.1016/j.nantod.2023.101884. Epub 2023 Jun 1. PMID: 37484164; PMCID: PMC10357922.

8. Zhang F, Parayath NN, Ene CI, Stephan SB, Koehne AL, Coon ME, Holland EC, Stephan MT. Genetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers. Nat Commun. 2019 Sep 3;10(1):3974. doi: 10.1038/s41467-019-11911-5. PMID: 31481662; PMCID: PMC6722139.