The tropomyosin receptor kinase (TRK) family of enzymes are transmembrane receptor tyrosine kinases (RTKs) that regulate synaptic strength and plasticity in the mammalian nervous system. There are three members of the TRK family: TRKA (encoded by NTRK1 gene), TRKB (NTRK2), and TRKC (NTRK3), which have all been implicated in the initiation and progression of malignancies[2]. RTKs are key regulators of tumor development as well as metastasis, aiding in the epithelial-mesenchymal transition, migration and angiogenesis. c-Kit, a stem cell factor receptor, is over-expressed or mutated, in small cell lung cancer, mast cell leukemia, seminoma, acute myeloid leukemia and most commonly in GIST patients and VEGFR-2 (KDR) has been shown to play an important role in the regulation of tumor angiogenesis[3]. MGCD516 (Sitravatinib) is a broad-spectrum multi-kinase inhibitor targeting multiple RTKs involved in driving sarcoma cell growth with IC50s of 6 nM, 1.5 nM, 2 nM, 2 nM, 5 nM, 6 nM, 6 nM, 8 nM, 0.5 nM, 29 nM, 5 nM, and 9 nM for Axl, MER, VEGFR3, VEGFR2, VEGFR1, KIT , FLT3, DDR2, DDR1, TRKA, TRKB and c-KIT respectively[4]. MGCD516 treatment can result in significant down-regulation of RTK phosphorylation including the canonical RTKs PDGFRα, PDGFRβ, IGF1-R and c-Met. In vitro colony-forming study, KLN205 and E0771 cell lines grown in normal growth performed with sitravatinib at the indicated doses (range from 10-4 to 1 μM), which showed IC50 of Sitravatinib is approximately 1 μM and antitumor activity that caused by Sitravatinib was not due to direct tumor cell killing but related to microenvironmental changes. In a vivo study, DBA/2 mice were injected 0.5 × 106 murine lung cancer (KLN205) cells subcutaneously then orally administrated with Sitravatinib at 20 mg/kg once per day for 30 days. The result showed that sitravatinib significantly inhibited tumor progression and induced tumor regression. Furthermore, treatment with sitravatinib reduced tumor-induced splenomegaly, suggestive of immune modulatory activity[5].
作用机制
Sitravatinib binds to the hinge region and forms a hydrogen bond with Met1160. The central difluorophenyl ring is in a hydrophobic pocket formed by Lys1110, Leu1157 and the terminal para-fluoro phenyl ring binds in the allosteric pocket between the DFG motif and α-C-helix.
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