生物活性

• 靶点	MCT1 Ki:1.6nM

• 描述Tumors efflux lactate can maintain glycolytic flux and prevent intracellular acidification via the monocarboxylate transporter (MCT) family, including MCT1-4 lactate transporters. AZD3965 is an inhibitor of MCT1 with Ki value of 1.6nM and pKi value of 8.8. The DLBCL, NHLcell lines demonstrated exquisite monotherapy sensitivity to AZD3965 with GI50 value below 100nM as well as the Raji, SU-DHL-10 and WSU-DLCL-2 cell lines which further demonstrated high MCT1 protein expression without MCT4. WSU-DLCL-2, SU-DHL-10 and TMD8 cell lines exposed to 100nM AZD3965 showed the lowest MCT1 expression level of TMD8 while it's positive for both MCT1 and MCT4 expression in the other cells , suggesting the association between sensitivity of this compound with MCT1 expression level . AZD3965 at concentration of 100nM significantly upregulated key glycolytic and gluconeogenic intermediates in Karpass-422 and WSU-DLCL-2 cell lines . Treatment with AZD3965 at 100nM caused increased intracellular lactate and decreased lactate uptake in DMS114, H526 and HGC27 cell lines. Exposure to 1µM AZD3965 led 50% reduction in cellular ATP under anoxia condition while 30% under normoxia condition, suggesting the effect of this compound on cellular redox and cause oxidative stress. Administration of AZD3965 delayed tumor growth in mice bearing H526 tumor, with a significant link between survival and tumor size. Meanwhile, an in vivo inhibition of lactate transport, indicated by higher concentrations of tumor lactate, could be observed. A phase I evaluation illuminated AZD3965 sensitivity variation in vitro in hypoxia condition. In the TMA, high MCT1 expression means worse prognosis which have provided a rationale test for AZD3965 in SCLC patients .

• 动物研究
  剂量	Mice[2] (p.o.): 100 mg/kg
  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
  NCT01791595	Adult Solid Tumor ... more >> Diffuse Large B Cell Lymphoma Burkitt Lymphoma Collapse <<	Phase 1	Recruiting	-	United Kingdom ... more >> Royal Marsden Hospital Active, not recruiting Sutton, London, United Kingdom, SM2 5PT The Beatson West of Scotland, Glasgow Recruiting Glasgow, United Kingdom Principal Investigator: Pam McKay, Dr          Leicester Royal Infirmary Recruiting Leicester, United Kingdom Principal Investigator: Martin Dyer, Prof.          The Christie Recruiting Manchester, United Kingdom Principal Investigator: Kim Linton, Dr          Freeman Hospital Active, not recruiting Newcastle upon Tyne, United Kingdom, NE7 7DN Derriford Hospital Recruiting Plymouth, United Kingdom Principal Investigator: Simon Rule, Prof. Collapse <<