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.
Assess cell survival rate under coculture conditions, finding that Hepa1-6-OE-MerTK cells showed increased survival rate over time
Cell Rep Med. 2024 Feb 20;5(2):101415.
Ba/F3 cells
100 nM
72 hours
Screening for drugs active against D1228X or Y1230X secondary mutations, revealing that Sitravatinib and other four type II MET-TKIs inhibited growth by less than 50% in D1228A/Y mutant cells.
J Hematol Oncol. 2022 Jun 11;15(1):79.
HEK293/ABCG2-482-R2
3 µM
72 hours
Restore the antineoplastic effect of ABCG2 substrates
Front Oncol. 2020 May 12;10:700.
S1-M1-80
3 µM
72 hours
Restore the antineoplastic effect of ABCG2 substrates
Front Oncol. 2020 May 12;10:700.
NCI-H460/MX20
3 µM
72 hours
Restore the antineoplastic effect of ABCG2 substrates
Front Oncol. 2020 May 12;10:700.
Saos2
1.5–2.0 μmol/L
72 hours
MGCD516 treatment resulted in significant blockade of phosphorylation of potential driver RTKs and induced potent anti-proliferative effects
Oncotarget. 2016 Jan 26;7(4):4093-109.
A673
1.5–2.0 μmol/L
72 hours
MGCD516 treatment resulted in significant blockade of phosphorylation of potential driver RTKs and induced potent anti-proliferative effects
Oncotarget. 2016 Jan 26;7(4):4093-109.
MPNST
250-750 nmol/L
72 hours
MGCD516 treatment resulted in significant blockade of phosphorylation of potential driver RTKs and induced potent anti-proliferative effects
Oncotarget. 2016 Jan 26;7(4):4093-109.
LS141
250-750 nmol/L
72 hours
MGCD516 treatment resulted in significant blockade of phosphorylation of potential driver RTKs and induced potent anti-proliferative effects
Oncotarget. 2016 Jan 26;7(4):4093-109.
DDLS
250-750 nmol/L
72 hours
MGCD516 treatment resulted in significant blockade of phosphorylation of potential driver RTKs and induced potent anti-proliferative effects
Oncotarget. 2016 Jan 26;7(4):4093-109.
BaF3-FLT3-ITD-F691L cells
3 nM
4 hours
Evaluate the inhibitory effect of Sitravatinib on BaF3-FLT3-ITD-F691L cell signaling pathways, results showed Sitravatinib effectively inhibited the signaling pathways of FLT3-ITD-F691L mutant cells
Biomark Res. 2023 Jan 24;11(1):8.
MOLM13 cells
1.511 nM
48 hours
Evaluate the inhibitory effect of Sitravatinib on MOLM13 cell proliferation, results showed Sitravatinib significantly inhibited the proliferation of FLT3-ITD AML cell lines
Biomark Res. 2023 Jan 24;11(1):8.
MV4-11 cells
0.556 nM
48 hours
Evaluate the inhibitory effect of Sitravatinib on MV4-11 cell proliferation, results showed Sitravatinib significantly inhibited the proliferation of FLT3-ITD AML cell lines
Biomark Res. 2023 Jan 24;11(1):8.
HEK293/ABCC10 cells
3 µmol/L
72 hours
Evaluate the reversal effect of Sitravatinib on ABCC10-mediated multidrug resistance, results showed that Sitravatinib partially reversed the resistance of HEK293/ABCC10 cells to paclitaxel
Cancer Commun (Lond). 2020 Jul;40(7):285-300.
HEK293/ABCB1 cells
3 µmol/L
72 hours
Evaluate the reversal effect of Sitravatinib on ABCB1-mediated multidrug resistance, results showed that Sitravatinib significantly reduced the IC50 values of paclitaxel, doxorubicin, and vincristine in HEK293/ABCB1 cells
Cancer Commun (Lond). 2020 Jul;40(7):285-300.
SW620/Ad300 cells
3 µmol/L
72 hours
Evaluate the reversal effect of Sitravatinib on ABCB1-mediated multidrug resistance, results showed that Sitravatinib significantly reduced the IC50 values of paclitaxel, doxorubicin, and vincristine in SW620/Ad300 cells
Cancer Commun (Lond). 2020 Jul;40(7):285-300.
KB-C2 cells
3 µmol/L
72 hours
Evaluate the reversal effect of Sitravatinib on ABCB1-mediated multidrug resistance, results showed that Sitravatinib significantly reduced the IC50 values of paclitaxel, doxorubicin, and vincristine in KB-C2 cells
Cancer Commun (Lond). 2020 Jul;40(7):285-300.
Bone marrow-derived macrophages (BMDMs)
12.5, 50, 200, 800 nM
2 hours (LPS stimulation) or 18 hours (IL-4 stimulation)
Sitravatinib dose-dependently inhibited the IL-4 plus CM–mediated expression of Arg1, Ym-1, and Fizz1, markers associated with an immunosuppressive macrophage phenotype, but did not affect the LPS plus CM–induced expression of Tnfα, Il-6, or Il-12, markers of an immunostimulatory macrophage phenotype.
JCI Insight. 2018 Nov 2;3(21):e124184.
Bone marrow–derived macrophages (BMDMs)
12.5, 50, 200, 800 nM
2 hours (LPS) or 18 hours (IL-4)
To evaluate the effect of sitravatinib on macrophage polarization. Results showed that sitravatinib dose-dependently inhibited the IL-4 plus CM–mediated expression of Arg1, Ym-1, and Fizz1 (markers associated with an immunosuppressive macrophage phenotype) but did not affect the LPS plus CM–induced expression of Tnfα, Il-6, or Il-12 (markers of an immunostimulatory macrophage phenotype).
JCI Insight. 2018 Nov 2;3(21):e124184.
Sitravatinib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NSG mice
MOLM13 xenograft model
Oral gavage
20 mg/kg
Once daily for 14 days
Evaluate the anti-tumor effect of Sitravatinib in the MOLM13 xenograft model, results showed Sitravatinib significantly prolonged the survival time of mice
Biomark Res. 2023 Jan 24;11(1):8.
C57BL/6 mice
Subcutaneous Hepa1-6 tumor model
Oral
20 mg/kg
6 days per week for 25 days
Evaluate the antitumor effect of sitravatinib combined with anti-PD-L1 antibody, finding that the combination therapy significantly inhibited tumor growth
Cell Rep Med. 2024 Feb 20;5(2):101415.
Crl:NU(NCr)-Foxn1nu nude mice
TNBC xenograft model
Oral
10 mg/kg/day
Continuous treatment: 6 days a week for several weeks; Alternating treatment: two days single drug, two days combined, two days single drug.
Evaluate the efficacy of Sitravatinib combined with Abemaciclib in TNBC xenograft models, showing significant suppression of tumor growth.
Cancers (Basel). 2024 Jun 18;16(12):2253.
ICR/SCID mice
MPNST and LS141 xenograft models
Oral
15 mg/kg
Once daily, 5 days a week for 3 weeks
MGCD516 treatment resulted in significant suppression of tumor growth compared to vehicle control as well as compared against imatinib and crizotinib
Oncotarget. 2016 Jan 26;7(4):4093-109.
Mice
KLN205, CT1B-A5, and E0771 tumor models
Oral
20 mg/kg
Once daily for 6 days or 2.5 weeks
Sitravatinib significantly inhibited tumor progression and induced tumor regression, reduced the number of tumor-associated immunosuppressive myeloid cells, increased the number of CD4+ T cells and exhausted CD8+ T cells, and enhanced the efficacy of PD-1 blockade.
JCI Insight. 2018 Nov 2;3(21):e124184.
Nude mice
SW620/Ad300 xenograft model
Oral administration
2 mg/kg
Every other day for 14 days
Evaluate the reversal effect of Sitravatinib combined with vincristine on ABCB1-mediated multidrug resistance, results showed that the combination therapy significantly inhibited the growth of SW620/Ad300 xenograft tumors
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