Uses
Pexidartinib is RTK inhibitor. It can be used in pharmacological activity, therapeutic use, and biological study of inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition.
Definition
ChEBI: Pexidartinib is a pyrrolopyridine that is 5-chloro-1H-pyrrolo[2,3-b]pyridine which is substituted by a [6-({[6-(trifluoromethyl)pyridin-3-yl]methyl}amino)pyridin-3-yl]methyl group at position 3. It is a potent multi-targeted receptor tyrosine kinase inhibitor of CSF-1R, KIT, and FLT3 (IC50 of 20 nM, 10 nM and 160 nM, respectively). Approved by the FDA for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT). It has a role as an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor and an antineoplastic agent. It is a pyrrolopyridine, an organochlorine compound, an aminopyridine, an organofluorine compound and a secondary amino compound.
General Description
Class: receptor tyrosine kinase;
Treatment: TGCT;
Other name: PLX3397;
Elimination half-life = 26.6 h;
Protein binding = >99%
Clinical Use
Pexidartinib is used for the treatment of adult patients with symptomatic tenosynovial giant cell tumour (TGCT) associated with severe morbidity or functional limitation not ameliorated by surgery.
Synthesis
Synthesis of PLX3397 (Pexidartinib)
in vitro
plx3397 strongly dampened the systemic and local accumulation of macrophages driven by b16f10 melanomas, without affecting gr-1+ myeloid derived suppressor cells [1].
in vivo
wild-type c57 mice were orthotopically injected with gl261 cells and fed with plx3397 compound. after 2 wks, tumors in the control group showed extensive microglia infiltration. in animals fed plx3397, however, there was a substantial reduction in the number of iba1- positive cells at the tumor [2].
target
Primary targets: CSF1R, KIT, FLT3
References
1)?DeNardo?et al.?(2011)?Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy;?Cancer Discov.?1?54
2)?Mok?et al.?(2014)?Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy;?Cancer Res.74?15
3)Sluijter?et al.?(2014)?Inhibition of CSF-1R supports T-cell mediated melanoma therapy;?PLoS One?9?e104230
4)?Peranzoni?et al.?(2018)?Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment;?Proc. Natl. Acad. Sci. USA?115?E4041
5)?Shi?et al.?(2019)?Modulating the Tumor Microenvironment via Oncolytic Viruses and CSF-1R Inhibition Synergistically Enhances Anti-PD-1 Immunotherapy;?Mol. Ther.?27?244
6) Dammeijer?et al.?(2017)?Depletion pf Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy;?Cancer Immunol. Res.?5?535
