生物活性

• 描述The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival. LY3023414 is a complex fused imidazoquinolinone with high solubility across a wide pH range designed to inhibit class I PI3K isoforms and mTOR kinase. The IC50 values of LY3023414 towards PI3K family members are 6.07 nM, 77.6 nM, 38 nM, 23.8 nM, 4.24 nM and 165 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, DNA-PK and mTOR, respectively. The compound is a novel, potent ATP-competitive inhibitor that demonstrates activity against PI3K, mTOR, and DNA-PK, thereby inducing cell-cycle effects and inhibiting cancer cell viability. Downstream target inhibition by LY3023414 occurs rapidly via an intermittent “on/off” mechanism that may enhance the drug's clinical tolerability, which may in turn allow LY3023414 to overcome some of the toxicities associated with PI3K/mTOR inhibitors and potentially reduce the emergence of feedback mechanisms leading to resistance. In vitro, inhibition of PI3K/AKT/mTOR signaling by LY3023414 caused G1 cell-cycle arrest and resulted in broad antiproliferative activity in cancer cell panel screens. In vivo, LY3023414 demonstrated high bioavailability and dose-dependent dephosphorylation of PI3K/AKT/mTOR pathway downstream substrates such as AKT, S6K, S6RP, and 4E-BP1 for 4 to 6 hours. In vivo mouse studies, LY3023414 was formulated in 1% HEC in distilled water containing 0.25% polysorbate 80 and 0.05% Dow-Corning Antifoam 1510-US and administered by oral gavage (final volume 0.2 mL) at 3, 6, or 10 mg/kg twice daily for 28 days which resulted in dose-responsive inhibition of tumor growth in the PTEN-deleted U87 MG xenograft model^[4].
• 作用机制The compound binds in a pocket bounded by side-chain residues of Met953 and Ile963 on one side and Trp812 and Ile831 on the other. It makes a hydrogen bond with the main-chain amide of Val882 and a CH···O interaction with the main-chain carbonyl of Glu880. It additionally interacts with the tyrosine hydroxyl of Tyr867 and the main-chain amide and side-chain of Asp964^[4].

• 动物研究
  剂量	Mice: 25 mg/kg[3] (p.o.); 6 mg/kg[1] (i.v.) Rat: 10 mg/kg[1] (p.o.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Mice Rats Dogs Dose 6 mg/kg 3 mg/kg (i.v.) 10 mg/kg (p.o.) 3 mg/kg Administration i.v. i.v. p.o. i.v. p.o. AUC0→inf 4580 ng·h/ml 5010 ± 765 ng/ml (i.v.) 4920 ± 604 ng/ml (p.o.) AUC0→24h 4570 ng·h/ml 2300 ± 143 ng·h/ml (i.v.) 7420 ± 1280 ng·h/ml (p.o.) 5010 ± 765 ng/ml (i.v.) 4920 ± 604 ng/ml (p.o.) T1/2 2.8 h 1.4 ± 0.2 (i.v.) 2.1 ± 0.5 (p.o.) 1.0 ± 0.3 (i.v.) 1.1 ± 0.1 (p.o.) Tmax 0.3 ± 0.1 (p.o.) 0.9 ± 0.8 (p.o.) AUC0-inf 2300 ± 137 ng·h/ml (i.v.) 7420 ± 1280 ng·h/ml (p.o.) CL 22 ml/min/kg 22 ± 1 ng/ml (i.v.) 10 ± 2 ng/ml (i.v.) Cmax 5410 ng/ml 1714 ± 308 ng/ml (i.v.) 3300 ± 492 ng/ml (p.o.) 3018 ± 614 ng/ml (i.v.) 1320 ± 261 ng/ml (p.o.) Vdss 2560 ml/kg 2760 ± 317 ml/kg (i.v.) 1200 ± 164 ml/kg (i.v.) F 97 ± 15% (p.o.) 100 ± 19% (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
  NCT02784795	Solid Tumor B... more >>reast Cancer Colon Cancer Cholangiocarcinoma Soft Tissue Sarcoma Collapse <<	Phase 1	Active, not recruiting	January 31, 2019	United States, Florida ... more >> Sylvester Comprehensive Cancer Center Miami, Florida, United States, 33136 United States, Michigan Karmanos Cancer Institute Detroit, Michigan, United States, 48201 United States, New York Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065 United States, Texas University of Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Denmark Rigshospitalet Copenhagen, København Ø, Denmark, 2100 France Institut Bergonie Bordeaux, France, 33076 Centre Leon Berard Lyon Cedex 08, France, 69373 Gustave Roussy Villejuif Cedex, France, 94805 Spain Hospital Universitari Vall d'Hebron Barcelona, Spain, 08035 Fundacion Jimenez Diaz Madrid, Spain, 28040 Hospital Madrid Norte Sanchinarro Madrid, Spain, 28050 Collapse <<
  NCT03155620	Advanced Malignant Solid Neopl... more >>asm Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma Childhood Langerhans Cell Histiocytosis Histiocytic Sarcoma Juvenile Xanthogranuloma Malignant Glioma Recurrent Central Nervous System Neoplasm Recurrent Childhood Ependymoma Recurrent Childhood Malignant Germ Cell Tumor Recurrent Childhood Medulloblastoma Recurrent Childhood Non-Hodgkin Lymphoma Recurrent Childhood Rhabdomyosarcoma Recurrent Childhood Soft Tissue Sarcoma Recurrent Ewing Sarcoma Recurrent Glioma Recurrent Hepatoblastoma Recurrent Langerhans Cell Histiocytosis Recurrent Malignant Solid Neoplasm Recurrent Neuroblastoma Recurrent Osteosarcoma Recurrent Peripheral Primitive Neuroectodermal Tumor Recurrent Rhabdoid Tumor Refractory Central Nervous System Neoplasm Refractory Childhood Malignant Germ Cell Tumor Refractory Ewing Sarcoma Refractory Glioma Refractory Hepatoblastoma Refractory Langerhans Cell Histiocytosis Refractory Malignant Solid Neoplasm Refractory Medulloblastoma Refractory Neuroblastoma Refractory Non-Hodgkin Lymphoma Refractory Osteosarcoma Refractory Peripheral Primitive Neuroectodermal Tumor Refractory Rhabdoid Tumor Refractory Rhabdomyosarcoma Rhabdoid Tumor Stage III Osteosarcoma AJCC v7 Stage III Soft Tissue Sarcoma AJCC v7 Stage IV Osteosarcoma AJCC v7 Stage IV Soft Tissue Sarcoma AJCC v7 Stage IVA Osteosarcoma AJCC v7 Stage IVB Osteosarcoma AJCC v7 Wilms Tumor Collapse <<	Phase 2	Recruiting	September 30, 2027	-
  NCT02124148	Neoplasm Metastasis ... more >> Colorectal Neoplasms Breast Cancer Collapse <<	Phase 1	Recruiting	February 27, 2020	United States, Florida ... more >> Florida Cancer Specialists Recruiting Sarasota, Florida, United States, 34232 Contact    9413779993       Principal Investigator: Manish Rajni Patel          United States, Oklahoma University of Oklahoma Health Sciences Center Recruiting Oklahoma City, Oklahoma, United States, 73104 Contact    405-271-4022       Principal Investigator: Kathleen Moore          United States, Tennessee Sarah Cannon Research Institute SCRI Recruiting Nashville, Tennessee, United States, 37203 Contact    615-329-7615       Principal Investigator: SMO Sarah Cannon Research Inst.          Tennessee Oncology PLLC Recruiting Nashville, Tennessee, United States, 37203 Contact    6153297274       Principal Investigator: Johanna Chock Bendell          United States, Texas University of Texas MD Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact    713-563-5844       Principal Investigator: David S Hong Collapse <<

• 更多
• 参考文献

• [1] Smith MC, Mader MM, et al. Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth. Mol Cancer Ther. 2016 Oct;15(10):2344-2356.

  [2] Zaidi AH, Kosovec JE, et al. PI3K/mTOR Dual Inhibitor, LY3023414, Demonstrates Potent Antitumor Efficacy Against Esophageal Adenocarcinoma in a Rat Model. Ann Surg. 2017 Jul;266(1):91-98.

  [3] Zheng L, Li H, et al. Autophagy inhibition sensitizes LY3023414-induced anti-glioma cell activity in vitro and in vivo. Oncotarget. 2017 Oct 27;8(58):98964-98973.

  [4] Smith MC, Mader MM, Cook JA, Iversen P, Ajamie R, Perkins E, Bloem L, Yip YY, Barda DA, Waid PP, Zeckner DJ, Young DA, Sanchez-Felix M, Donoho GP, Wacheck V. Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth. Mol Cancer Ther. 2016 Oct;15(10):2344-2356.