Pexidartinib HCl
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MedKoo CAT#: 207104

CAS#: 2040295-03-0 (HCl)

Description: Pexidartinib, also known 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

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Pexidartinib HCl
CAS# 2040295-03-0 (HCl)
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 207104
Name: Pexidartinib HCl
CAS#: 2040295-03-0 (HCl)
Chemical Formula: C20H16Cl2F3N5
Exact Mass: 0.00
Molecular Weight: 454.280
Elemental Analysis: C, 52.88; H, 3.55; Cl, 15.61; F, 12.55; N, 15.42

Price and Availability

Size Price Availability Quantity
100mg USD 150 Ready to ship
200mg USD 250 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
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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 HCl; Pexidartinib hydrochloride; 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 hydrochloride

InChi Key: CJLUYLRKLUYCEK-UHFFFAOYSA-N

InChi Code: InChI=1S/C20H15ClF3N5.ClH/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);1H

SMILES Code: FC(C1=CC=C(CNC2=NC=C(CC3=CNC4=NC=C(Cl)C=C43)C=C2)C=N1)(F)F.[H]Cl

Appearance: 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

Shelf Life: >3 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:

Biological target: Pexidartinib hydrochloride (PLX-3397 hydrochloride) is a potent, orally active, selective, and ATP-competitive colony stimulating factor 1 receptor (CSF1R or M-CSFR) and c-Kit inhibitor. Pexidartinib hydrochloride has IC50 values of 10 nM (c-Kit) and 20 nM (cFMS).
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: This study tested whether attenuating the inflammatory responses could mitigate thyroid cancer progression. The mice were treated with an inhibitor of colony-stimulating factor 1 receptor (CSF1R), pexidartinib (PLX-3397; PLX). CSF1R mediates the activity of the cytokine, colony stimulating factor 1 (CSF1), in the production, differentiation, and functions of monocytes and macrophages. Treatment of PLX3397 (Pexidartinib; BOC Sciences Shirley, NY) was started from 6- to 7-weeks old. Mice were given PLX3397 doses of 50 mg/kg via oral gavage daily for 10 days. PLX3397 was dissolved in 10% DMSO and corn oil (sigma-Aldrich, St. Louis, MO). Treatment with PLX decreased 94% and 62% of inflammatory monocytes in the thyroid and bone marrow, respectively, versus controls. Further, PLX suppressed the expression of critical cytokine and inflammation-regulating genes such as Csf1r, SPP1 (OPN), Aif1, IL6, Ccl9, Ccl3, Ccl12, and Ccr2 (25%-80%), resulting in inhibition of 89% tumor cell proliferation, evidenced by Ki-67 immunostaining. These preclinical findings suggest that inflammation occurs in the early stage of thyroid carcinogenesis and plays a critical in cancer progression. Importantly, attenuation of inflammation by inhibitors such as PLX would be beneficial in preventing thyroid cancer. Am J Cancer Res. 2020; 10(6): 1857–1870.Published online 2020 Jun 1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339265/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 60.0 132.10

Preparing Stock Solutions

The following data is based on the product molecular weight 454.28 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.Park S, Kim M, Zhu J, Lee WK, Altan-Bonnet G, Meltzer P, Cheng SY. Inflammation suppression prevents tumor cell proliferation in a mouse model of thyroid cancer. Am J Cancer Res. 2020 Jun 1;10(6):1857-1870. PMID: 32642296; PMCID: PMC7339265. 2. 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. PMID: 30796225; PMCID: PMC6385215.
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.Park S, Kim M, Zhu J, Lee WK, Altan-Bonnet G, Meltzer P, Cheng SY. Inflammation suppression prevents tumor cell proliferation in a mouse model of thyroid cancer. Am J Cancer Res. 2020 Jun 1;10(6):1857-1870. PMID: 32642296; PMCID: PMC7339265. 2. 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. PMID: 30796225; PMCID: PMC6385215.

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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.