生物活性

• 靶点	mTOR IC50:1nM

• 描述mTOR kinase, a key oncogenic signalling molecules, is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer, which assembles with either raptor or rictor to form two distinct complexes: mTORC1 and mTORC2. Sapanisertib (INK 128, MLN0128), derived from the PP242 chemical scaffold (Ki=1.4nM), is a potent and selective mTOR inhibitor with IC50 value of 1nM. Using either PP242 or INK128, a selective decrease in the expression of YB1, MTA1, vimentin and CD44 at the protein level in PC3 cells starting at 6 h of treatment was observed. Furthermore, INK128 inhibits cancer cell migration starting at 6 h of treatment. Notably, knockdown of 4EBP1 and 4EBP2 in PC3 cells or using 4EBP1 and 4EBP2 double knockout MEFs reduced the ability of INK128 to decrease expression of these pro-invasion mRNAs. In a preclinical trial INK128 in Pten^L/L mice, 4EBP1 and p70S6K1/2 phosphorylation was completely restored to wild-type levels after treatment with INK128, which resulted in a 50% decrease in PIN lesions as well as proliferation inhibition and a ten-fold increase in apoptosis. In a ZR-75-1 breast cancer xenograft model, 0.3 mg/kg/day of orally INK128 exhibited tumor growth inhibition efficacy . Both the phosphorylation of S6 and 4EBP1 can be greatly inhibited by INK 128 while AKT phosphorylation at Ser473 can be selectively inhibited, they are the downstream substrate of TORC1/2, respectively. Furthermore, INK 128 also shows potent inhibition effects on cell lines resistant to rapamycin and pan-PI3K inhibitors . PANC-1 and MIA PaCa-2 cell lines treated with concentrations range of 1-100nM of INK-128 were significant inhibited time independently after incubated for 72h. With the concentrations range of 10-100nM, PANC-1 cell apoptosis was induced at 72h while cell cycle progression was disrupted at 50nM after incubation for 48h. Beside, gemcitabine sensitivity increased at 10nM for 72h.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  MIA PaCa-2	1-100 nM	Cell Viability Assay	72 h	inhibits cell viability dose dependently	24971544
  PANC-1	1-100 nM	Cell Viability Assay	72 h	inhibits cell viability dose dependently	24971544
  PANC-1	50 nM	Cell Viability Assay	24-96 h	inhibits cell viability time dependently	24971544

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• 动物研究
  剂量	Nude Mice: 1 mg/kg - 3 mg/kg[3] (p.o.), 0.5 mg/kg - 7 mg/kg[4] (i.p.), 0.3 mg/kg[5] (i.p.)
  给药途径	p.o., i.p.

• 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
  NCT02159989	Advanced Malignant Solid Neopl... more >>asm Fibrolamellar Carcinoma Metastatic Malignant Solid Neoplasm Ovarian Carcinoma Pancreatic Neuroendocrine Tumor Recurrent Malignant Solid Neoplasm Refractory Malignant Solid Neoplasm Unresectable Solid Neoplasm Collapse <<	Phase 1	Recruiting	-	United States, Texas ... more >> M D Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact: Aung Naing    713-792-3245       Principal Investigator: Aung Naing Collapse <<
  NCT02601209	High Grade Sarcoma ... more >> Metastatic Leiomyosarcoma Metastatic Malignant Peripheral Nerve Sheath Tumor Metastatic Synovial Sarcoma Metastatic Undifferentiated Pleomorphic Sarcoma Myxofibrosarcoma Recurrent Leiomyosarcoma Recurrent Malignant Peripheral Nerve Sheath Tumor Recurrent Synovial Sarcoma Recurrent Undifferentiated Pleomorphic Sarcoma Stage III Uterine Corpus Leiomyosarcoma AJCC v8 Stage IIIA Uterine Corpus Leiomyosarcoma AJCC v8 Stage IIIB Uterine Corpus Leiomyosarcoma AJCC v8 Stage IIIC Uterine Corpus Leiomyosarcoma AJCC v8 Stage IV Uterine Corpus Leiomyosarcoma AJCC v8 Stage IVA Uterine Corpus Leiomyosarcoma AJCC v8 Stage IVB Uterine Corpus Leiomyosarcoma AJCC v8 Collapse <<	Phase 1 Phase 2	Active, not recruiting	-	-
  NCT02417701	KEAP1 Gene Mutation ... more >> KRAS Gene Mutation NFE2L2 Gene Mutation Recurrent Squamous Cell Lung Carcinoma Stage IV Squamous Cell Lung Carcinoma AJCC v7 Collapse <<	Phase 2	Recruiting	-	United States, New Jersey ... more >> Memorial Sloan Kettering Basking Ridge Recruiting Basking Ridge, New Jersey, United States, 07920 Contact: Sree B. Chalasani    212-639-7592       Sub-Investigator: Sree B. Chalasani          Sub-Investigator: Loren S. Michel          Sub-Investigator: Han Xiao          Sub-Investigator: Afsheen Iqbal          Memorial Sloan Kettering Monmouth Recruiting Middletown, New Jersey, United States, 07748 Contact: Azadeh Namakydoust    212-639-7592       Sub-Investigator: Azadeh Namakydoust          Sub-Investigator: Jason A. Konner          Sub-Investigator: Colette N. Owens          Sub-Investigator: Serena T. Wong          Sub-Investigator: Marina Shcherba          United States, New York Memorial Sloan Kettering Commack Recruiting Commack, New York, United States, 11725 Contact: Jia Li    212-639-7592       Sub-Investigator: Jia Li          Sub-Investigator: Jahan Aghalar          Sub-Investigator: Avni M. Desai          Sub-Investigator: Juliana W. Eng          Sub-Investigator: John J. Fiore          Sub-Investigator: Stuart M. Lichtman          Sub-Investigator: Wanqing I. Zhi          Memorial Sloan Kettering Westchester Recruiting Harrison, New York, United States, 10604 Contact: Daniel C. McFarland    212-639-7592       Sub-Investigator: Daniel C. McFarland          Sub-Investigator: Parisa Momtaz          Sub-Investigator: Alice Zervoudakis          Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States, 10065 Contact: Paul K. Paik    646-888-4202    paikp@mskcc.org    Principal Investigator: Paul K. Paik          Memorial Sloan Kettering Rockville Centre Recruiting Rockville Centre, New York, United States, 11570 Contact: Arlyn J. Apollo    212-639-7592       Sub-Investigator: Arlyn J. Apollo          Sub-Investigator: Pamela R. Drullinsky          Sub-Investigator: Zoe Goldberg          Sub-Investigator: Tiffany Troso-Sandoval Collapse <<

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