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• 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.

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• 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.

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• 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.;

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