PLX3397 (Pexidartinib)

Application

Pexidartinib is a small-molecule, oral, potent multi-targeted receptor tyrosine kinase (RTK) inhibitor of CSF-1R, Kit, and Flt3 and it can cross the blood-brain barrier. In M-NFS-60, Bac 1.2F5 and M-07e cells, PLX3397 (Pexidartinib) inhibits the CSF1-dependent proliferation with IC50 of 0.44 μM, 0.22 μM and 0.1 μM, respectively. It has been reported that PLX3397 strongly attenuates systemic and local accumulation of macrophages driven by B16F10 melanoma and does not affect Gr-1+ bone marrow-derived suppressor cells. Besides, PLX3397 weakly inhibited the growth of SK-N-SH cells with an IC50 of 10 μM and had little effect on the growth of MDA-MB-231 human tumor cell xenografts. In MMTV-PyMT mice, pexidartinib (40 mg/kg, p.o.) significantly inhibits both steady-state and PTX-induced tumor infiltration by CD45 + CD11b + Ly6C − Ly6G − F4/80 +. Pexidartinib/PTX therapy also results in a significant reduction in CD31+ vessel density within mammary tumors, paralleling induction of apoptosis and necrosis.

Description

Pexidartinib (TURALIO™) is a novel, orally available small molecule tyrosine kinase inhibitor (TKI) with potent and selective activity against the colony-stimulating factor 1 (CSF1) receptor. Pexidartinib also inhibits KIT proto-oncogene receptor tyrosine kinase (KIT) and FMS-like tyrosine kinase 3 harboring an internal tandem duplication mutation (FLT3-ITD). Pexidartinib has been developed by Daiichi Sankyo for the treatment of tenosynovial giant cell tumor (TGCT; also known as giant cell tumor of the tendon sheath or pigmented villonodular synovitis.

Synthetic Routes

The synthetic routes of pexidartinib were developed by Daiichi Sankyo Company6. A novel efficient synthetic route for pexidartinib was designed via Tsuji–Trost/Heck tandem reaction in combination with palladium and silver catalysis, which avoids the need for ultra-low temperature and greatly reduces the amount of corrosive trifluoroacetic acid. The cheap and easily available materials and reagents and easy operations for workup and purification make this route more practical.

Anti-tumor Activity

Administration of PLX3397 reduced CIBP, induced substantial intratumoral fibrosis, and was also highly efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling. PLX3397 is superior to imatinib in the treatment of malignant peripheral nerve sheath tumor (MPNST), and the combination of PLX3397 with a TORC1 inhibitor could provide a new therapeutic approach for the treatment of this disease.

Description

Colony stimulating factor 1 (CSF1) is a cytokine that is involved in the recruitment and activation of tissue macrophages. It exerts these effects by binding to its corresponding receptor tyrosine kinase, the cFMS/CSF1 receptor (CSF1R). Pexidartinib is a brain-penetrant inhibitor of CSF1R, as well as c-Kit and FLT3 (IC₅₀s = 20, 10, and 160 nM in vitro, respectively). It has been used in combination with paclitaxel to block macrophage recruitment in mammary tumor-bearing mice, thus slowing primary tumor development and metastasis. Pexidartinib has also been used to block microglial stimulation of glioblastoma invasion in both cell culture and a mouse model of glioblastoma multiforme.

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.

brand name

Turalio

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.

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

storage

Store at -20°C

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