生物活性

• 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.

• 动物研究
  剂量	Mice: 10 mg/kg, 20 mg/kg[2] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02664935	Non-Small Cell Lung Cancer ... more >> Carcinoma, Squamous Cell Adenocarcinoma Collapse <<	Phase 2	Recruiting	September 2021	United Kingdom ... more >> Belfast City Hospital, Belfast Health and Social Care Trust Recruiting Belfast, United Kingdom Contact: Paula Scullin          Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust Recruiting Birmingham, United Kingdom, B15 2GW Contact: Gary Middleton, MB BS MD FRCP          Principal Investigator: Gary Middleton, MB BS MD FRCP          Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust Recruiting Birmingham, United Kingdom Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust Recruiting Cambridge, United Kingdom, CB2 0QQ Contact: David Gilligan, BSc (Hons) MB BChir FRCP FRCR       cctc@addenbrookes.nhs.uk    Principal Investigator: David Gilligan, BSc (Hons) MB BChir FRCP FRCR          Velindre Cancer Centre, Velindre NHS Trust Recruiting Cardiff, United Kingdom, CF14 2TL Contact: Alison Brewster, BSC MB BCh FRCR MD    029 2061 5888       Principal Investigator: Alison Brewster, BSC MB BCh FRCR MD          Edinburgh Cancer Centre, Western General Hospital Recruiting Edinburgh, United Kingdom, EH4 2XU Contact: Melanie Mackean, MB ChB MRCP MSc MD          Principal Investigator: Melanie Mackean, MB ChB MRCP MSc MD          Royal Devon and Exeter Hospital Recruiting Exeter, United Kingdom Contact: Elizabeth Toy          Principal Investigator: Elizabeth Toy          Cancer Research UK Clinical Trials Unit, Beatson West of Scotland Cancer Centre Recruiting Glasgow, United Kingdom, G12 0YN Contact: Noelle O'Rourke, BA MB MCh MA MCRP MD FRCR CCST          Principal Investigator: Noelle O'Rourke, BA MB MCh MA MCRP MD FRCR CCST          St. James' University Hospital, Leeds Teaching Hospital NHS Trust Recruiting Leeds, United Kingdom, LS9 7TF Contact: Clive Mulatero, BA MB BCh MA PhD FRCP          Principal Investigator: Clive Mulatero, BA MB BCh MA PhD FRCP          Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust Recruiting Leicester, United Kingdom Contact: Dean Fennell          Royal Marsden Hospital, The Royal Marsden NHS Foundation Trust Recruiting London, United Kingdom, SW3 6JJ Contact: Sanjay Popat          Principal Investigator: Sanjay Popat, BSc MB BS MRCP PhD FRCP          Charing Cross Hospital, Imperial College Healthcare NHS Trust Recruiting London, United Kingdom Contact: Conrad Lewanski          Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust Recruiting London, United Kingdom Contact: James Spicer          St Bartholomew's Hospital, Barts Health NHS Trust Recruiting London, United Kingdom Contact: John Conibear          University College Hospital, University College London Hospitals NHS Foundation Trust Recruiting London, United Kingdom The Christie Hospital, The Christie NHS Foundation Trust Recruiting Manchester, United Kingdom Contact: Yvonne Summers          Sir Bobby Robson Cancer Trial Research Centre, The Newcastle upon Tyne Hospitals Recruiting Newcastle, United Kingdom, NE7 7DN Contact: Alastair Greystoke          Principal Investigator: Alastair Greystoke, BSc MBChB MRCP MSc PhD          Churchill Hospital, Oxford University Hospitals NHS Foundation Trust Recruiting Oxford, United Kingdom Contact: Denis Talbot          Weston Park Hospital, Sheffield Teaching Hospitals NHS Foundation Trust Recruiting Sheffield, United Kingdom Contact: Sarah Danson          Southampton General Hospital, University Hospital Southampton NHS Foundation Trust Recruiting Southampton, United Kingdom, SO16 6YD Contact: Christian Ottensmeier       clinicaltrials@uhs.nhs.uk    Principal Investigator: Christian Ottensmeier Collapse <<
  NCT03015740	Malignant Neoplasms of Urinary... more >> Tract Other Disorders of Kidney and Ureter Renal Cell Carcinoma Collapse <<	Phase 1 Phase 2	Recruiting	April 2023	United States, Texas ... more >> University of Texas MD Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact       ntannir@mdanderson.org Collapse <<
  NCT03666143	Non-squamous, Non-small Cell L... more >>ung Cancer (NSCLC), Renal Cell Carcinoma (RCC), and Ovarian Cancer (OC) Collapse <<	Phase 1	Not yet recruiting	April 2021	Australia, New South Wales ... more >> Blacktown Cancer and Haematology Centre Not yet recruiting Blacktown, New South Wales, Australia Contact: Bo Gao          Australia, Queensland ICON Cancer Foundation Not yet recruiting South Brisbane, Queensland, Australia Contact: Jeffrey Goh          Australia, Victoria Austin Hospital Not yet recruiting Heidelberg, Victoria, Australia Contact: Hui Gan          Monash Health Not yet recruiting Melbourne, Victoria, Australia Contact: Benjamin Markman          Nucleus Network Not yet recruiting Melbourne, Victoria, Australia Contact: Mark Voskoboynik          Australia, Western Australia Linear Clinical Research Limited Not yet recruiting Perth, Western Australia, Australia Contact: Michael Millward          China, Beijing Beijing Cancer Hospital Not yet recruiting Beijing, Beijing, China Contact: Jun Guo          Cancer Hospital Chinese Academy of Medical Science Not yet recruiting Beijing, Beijing, China Contact: Aiping Zhou          Peking University First Hospital Not yet recruiting Beijing, Beijing, China Contact: Zhisong He          China, Guangdong Guangdong General Hospital Not yet recruiting Guangzhou, Guangdong, China Contact: Qing Zhou          Sun Yat-Sen University Cancer Center Not yet recruiting Guangzhou, Guangdong, China Contact: Fangjian Zhou          China, Jilin The First Hospital of Jilin University Not yet recruiting Changchun, Jilin, China Contact: Jiuwei Cui          China, Shanghai Renji Hospital Shanghai Jiaotong University School of Medicine Not yet recruiting Shanghai, Shanghai, China Contact: Yiran Huang          China, Tianjin Tianjin Medical University Cancer Institute & Hospital Not yet recruiting Tianjin, Tianjin, China Contact: Dingzhi Huang          China, Zhejiang Zhejiang Cancer Hospital Not yet recruiting Hangzhou, Zhejiang, China Contact: Xinmin Yu          China Beijing Cancer Hospital Not yet recruiting Beijing, China Contact: Jun Zhao Collapse <<

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• 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.

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