产品说明书

Sitravatinib

Print
Chemical Structure| 1123837-84-2 同义名 : MGCD516;MG-516
CAS号 : 1123837-84-2
货号 : A314800
分子式 : C33H29F2N5O4S
纯度 : 99%+
分子量 : 629.676
MDL号 : MFCD28502181
存储条件：

粉末 Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 30 mg/mL(47.64 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
靶点

  • VEGFR1

    VEGFR1 (FLT1), IC50:6 nM

  • VEGFR3

    VEGFR3 (FLT4), IC50:2 nM

  • VEGFR2

    VEGFR2 (KDR), IC50:5 nM

  • c-Kit

    Kit, IC50:6 nM
描述 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.
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.59mL

0.32mL

0.16mL

7.94mL

1.59mL

0.79mL

15.88mL

3.18mL

1.59mL
参考文献

[1]Patwardhan PP, Ivy KS, et al. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget. 2016 Jan 26;7(4):4093-109.

[2]Yan W, Lakkaniga NR, Carlomagno F, Santoro M, McDonald NQ, Lv F, Gunaganti N, Frett B, Li HY. Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application. J Med Chem. 2019 Feb 28;62(4):1731-1760. doi: 10.1021/acs.jmedchem.8b01092. Epub 2018 Sep 19. Erratum in: J Med Chem. 2020 Sep 10;63(17):10089. PMID: 30188734; PMCID: PMC7875308.

[3]Patel JP, Kuang YH, Chen ZS, Korlipara VL. Inhibition of c-Kit, VEGFR-2 (KDR), and ABCG2 by analogues of OSI-930. Bioorg Med Chem Lett. 2011 Nov 1;21(21):6495-9. doi: 10.1016/j.bmcl.2011.08.070. Epub 2011 Aug 22. PMID: 21920748.

[4]Patwardhan PP, Ivy KS, Musi E, de Stanchina E, Schwartz GK. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget. 2016 Jan 26;7(4):4093-109. doi: 10.18632/oncotarget.6547. PMID: 26675259; PMCID: PMC4826192.

[5]Du W, Huang H, Sorrelle N, Brekken RA. Sitravatinib potentiates immune checkpoint blockade in refractory cancer models. JCI Insight. 2018 Nov 2;3(21):e124184. doi: 10.1172/jci.insight.124184. PMID: 30385724; PMCID: PMC6238734.