CAS No. : 1029044-16-3

Product Details
For research use only. Not Intended for Therapeutic Use!
Cat No:I000179
Synonyms:Pexidartinib; PLX-3397; PLX3397; 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine
Molecular Formula:C₂₀H₁₅ClF₃N₅
Molecular Weight:417.81
IC50:28/16 nM(Fms/Kit)
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Appearance:Yellow solid powder
Purity: > 98%
Cat No:I000179
Cas No:1029044-16-3

Pexidartinib(cas# 1029044-16-3), also known as PLX-3397, is a small-molecule receptor tyrosine kinase (RTK) inhibitor of KIT, CSF1R and FLT3 with potential antineoplastic activity. PLX3397 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.

Originator: Plexxikon
Developer: Array BioPharma; AstraZeneca; Barbara Ann Karmanos Cancer Institute; Centre Leon Berard; Columbia University; Memorial Sloan-Kettering Cancer Center; Merck & Co; National Cancer Institute (USA); Plexxikon; University of California at San Francisco
Class: 2 ring heterocyclic compounds; Antineoplastics; Fluorine compounds; Pyridines; Pyrroles; Small molecules
Mechanism of Action: Fms-like tyrosine kinase 3 inhibitors; Immunomodulators; Macrophage colony stimulating factor inhibitors; Protein kinase inhibitors; Proto oncogene protein c-kit inhibitors
Orphan Drug Status: Yes - Giant cell tumour of tendon sheath; Pigmented villonodular synovitis
New Molecular Entity: Yes
1. Cancer Immunol Res. 2017 Jul;5(7):535-546. doi: 10.1158/2326-6066.CIR-16-0309. Epub 2017 May 23.

Depletion of Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy.

Dammeijer F(1)(2), Lievense LA(1)(2)(3), Kaijen-Lambers ME(1)(2), van Nimwegen M(1), Bezemer K(1)(2), Hegmans JP(1)(2), van Hall T(4), Hendriks RW(1), Aerts JG(5)(2)(3).
Author information:
(1)Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands. (2)Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands. (3)Amphia Hospital, Breda, the Netherlands. (4)Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands. (5)Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.
New immunotherapeutic strategies are needed to induce effective antitumor immunity in all cancer patients. Malignant mesothelioma is characterized by a poor prognosis and resistance to conventional therapies. Infiltration of tumor-associated macrophages (TAM) is prominent in mesothelioma and is linked to immune suppression, angiogenesis, and tumor aggressiveness. Therefore, TAM depletion could potentially reactivate antitumor immunity. We show that M-CSFR inhibition using the CSF-1R kinase inhibitor PLX3397 (pexidartinib) effectively reduced numbers of TAMs, circulating nonclassical monocytes, as well as amount of neoangiogenesis and ascites in mesothelioma mouse models, but did not improve survival. When combined with dendritic cell vaccination, survival was synergistically enhanced with a concomitant decrease in TAMs and an increase in CD8+ T-cell numbers and functionality. Total as well as tumor antigen-specific CD8+ T cells in tumor tissue of mice treated with combination therapy showed reduced surface expression of the programmed cell death protein-1 (PD-1), a phenomenon associated with T-cell exhaustion. Finally, mice treated with combination therapy were protected from tumor rechallenge and displayed superior T-cell memory responses. We report that decreasing local TAM-mediated immune suppression without immune activation does not improve survival. However, combination of TAM-mediated immune suppression with dendritic cell immunotherapy generates robust and durable antitumor immunity. These findings provide insights into the interaction between immunotherapy-induced antitumor T cells and TAMs and offer a therapeutic strategy for mesothelioma treatment. Cancer Immunol Res; 5(7); 535-46. ©2017 AACR.

2. Clin Ther. 2016 Apr;38(4):778-93. doi: 10.1016/j.clinthera.2016.03.008. Epub 2016 Apr 1.

Patient-reported Symptoms of Tenosynovial Giant Cell Tumors.

Gelhorn HL(1), Tong S(2), McQuarrie K(3), Vernon C(3), Hanlon J(3), Maclaine G(4), Lenderking W(3), Ye X(5), Speck RM(3), Lackman RD(6), Bukata SV(7), Healey JH(8), Keedy VL(9), Anthony SP(10), Wagner AJ(11), Von Hoff DD(12), Singh AS(7), Becerra CR(13), Hsu HH(2), Lin PS(2), Tap WD(8).
Author information:
(1)Evidera, Bethesda, Maryland. Electronic address: (2)Plexxikon Inc, Berkeley, California. (3)Evidera, Bethesda, Maryland. (4)Daiichi Sankyo Development Ltd, Buckinghamshire, United Kingdom. (5)Daiichi Sankyo Pharma Development, Edison, New Jersey. (6)Cooper University Health Center, Orthopaedic Oncology Center, Camden, New Jersey. (7)Ronal Reagan UCLA Medical Center, Los Angeles, California. (8)Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York. (9)Vanderbilt University Medical Center, Hematology/Oncology, Nashville, Tennessee. (10)Texas Oncology-Tyler, Tyler, TX. (11)Dana-Farber Cancer Institute, Boston, Massachusetts. (12)HonorHealth & Translational Genomics Research Institute, Scottsdale, Arizona. (13)Sammons Cancer Center/US Oncology, Dallas, Texas.
PURPOSE: Tenosynovial giant cell tumor (TGCT), a rare locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, inflammation, pain, and swelling, in part due to colony-stimulating factor 1 receptor-bearing macrophages recruited to the tumor by genetic elevation of colony-stimulating factor 1 activity. The most common treatment is surgery, although promising pharmacologic treatments are in development. Patient-reported outcome (PRO) instruments are critical end points in demonstrating the clinical relevance of standard oncologic outcome measures and the overall impact of novel pharmacologic therapies in nonmalignant neoplastic conditions such as TGCT. The content validity of PROs relevant to patients with TGCT has not been formally investigated, and instruments to evaluate such outcomes do not exist for this condition.
METHODS: PRO instruments of potential relevance were evaluated by using a literature review and by clinical and PRO experts. Patients with TGCT were recruited through clinical sites and the Internet for participation in qualitative research interviews to identify predominant symptoms and to test the relevance and content validity of several PRO measures. Select PRO measures were included in a Phase I clinical trial, and preliminary results of the PRO end points are reported descriptively.
FINDINGS: Of the 22 subjects who participated in qualitative interviews, 73% were female, and their mean age was 42.5 years (range, 27-56 years). The TGCTs (19 diffuse and 3 localized) were located in the knee (n = 15), hip (n = 3), ankle (n = 2), elbow (n = 1), and forearm (n = 1). The most common symptoms cited were pain (82%), swelling (86%), stiffness (73%), reduced range of motion (64%), and joint instability (64%), which were consistent with clinical expert input and with the content of instruments chosen by PRO experts. The worst pain numeric rating scale, Patient Reported Outcomes Measurement Information System physical functioning items, and the Western Ontario and McMaster Universities Osteoarthritis Index, as well as a worst stiffness numeric rating scale developed for TGCT, were confirmed as meaningful measures of TGCT patient symptoms and were well understood in qualitative interviews. Results from the Phase I trial showed trends of improvement in both pain and stiffness over time. IMPLICATIONS: This study is the first to gather information directly from patients with TGCT regarding their symptom experiences. Pain, stiffness, and physical functioning are important treatment outcomes in patients with TGCT. We have identified content-valid PRO measures of these concepts, which are included in an ongoing Phase III TGCT clinical trial with pexidartinib (PLX3397) (NCT02371369).
3. Clin Cancer Res. 2014 Jun 15;20(12):3146-58. doi: 10.1158/1078-0432.CCR-13-2576. Epub 2014 Apr 9.
Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs.
Patwardhan PP(1), Surriga O(2), Beckman MJ(2), de Stanchina E(2), Dematteo RP(2), Tap WD(2), Schwartz GK(2).
Author information:
(1)Authors/' Affiliations: Jennifer Goodman Linn Laboratory of New Drug Development, Department of Medicine, Department of Molecular Pharmacology and Chemistry, Department of Surgery, Memorial Sloan Kettering Cancer Center; and Division of Hematology/Oncology, Columbia University Medical Center, New York, New York (2)Authors/' Affiliations: Jennifer Goodman Linn Laboratory of New Drug Development, Department of Medicine, Department of Molecular Pharmacology and Chemistry, Department of Surgery, Memorial Sloan Kettering Cancer Center; and Division of Hematology/Oncology, Columbia University Medical Center, New York, New York.
PURPOSE: Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive tumor type that is resistant to chemotherapy and there are no effective therapies. MPNSTs have been shown to have gene amplification for receptor tyrosine kinases (RTK), PDGFR and c-Kit. We tested the c-Kit inhibitor, imatinib, and PLX3397, a selective c-Fms and c-Kit inhibitor, to evaluate their efficacy against MPNST cells in vitro and in vivo.
EXPERIMENTAL DESIGN: We tested the efficacy of imatinib or PLX3397 either alone or in combination with TORC1 inhibitor rapamycin in a cell proliferation assay in vitro and by immunoblotting to determine target inhibition. Immunoblotting and immunohistochemical analysis was further carried out using xenograft samples in vivo.
RESULTS: Our in vitro studies show that imatinib and PLX3397 similarly inhibit cell growth and this can be enhanced with rapamycin with comparable target specificity. However, in vivo studies clearly demonstrate that compared with imatinib, PLX3397 results in sustained blockade of c-Kit, c-Fms, and PDGFRβ, resulting in significant suppression of tumor growth. Moreover, staining for Iba-1, a marker for macrophages, indicates that PLX3397 results in significant depletion of macrophages in the growing tumors. The combination of PLX3397 and rapamycin results in even greater macrophage depletion with continued growth suppression, even when the drug treatment is discontinued.
CONCLUSIONS: Taken together, our data strongly suggest that PLX3397 is superior to imatinib in the treatment of MPNSTs, and the combination of PLX3397 with a TORC1 inhibitor could provide a new therapeutic approach for the treatment of this disease.
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