生物活性

• 靶点	TLR8 EC50:100nM

• 描述The toll-like receptors (TLR) are a family of protein that are responsible for pathogen recognition. TLR8 is expressed within the endolysosomal compartmental pathway and it is able to recognize the intracellular pathogens^[3]. Motolimod is a novel small molecule TLR8 agonist with EC50 of about 100 nmol/L^[4]. The THP-1 cells were treated with motolimod from 3 nM to 10 μM overnight. The IL-1β and IL-18 mRNA level measured by RT-PCR were significantly increased after the treatment of motolimod. The IL-β, caspase-1 and pro-IL-1 protein level were also increased significantly as detected by western blotting assay^[5]. The hind paw of C57BL/6 mice was intradermally injected with 50 µg of motolimod and spontaneous pain behaviors were counted every 5 min for 30 min. It was found that the treatment of motolimod could induced lifting, flinching and licking in the first 15 min^[6].
• 作用机制Motolimod is an ultra-potent TLR8 selective agonist by binding with the TLR-8^[7].

• 动物研究
  剂量	Monkey: 1 mg/kg, 10 mg/kg[1] (s.c.)
  给药途径	s.c.

• 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
  NCT02650635	Colorectal Adenocarcinoma ... more >> Metastatic Pancreatic Adenocarcinoma Recurrent Breast Carcinoma Recurrent Colorectal Carcinoma Recurrent Melanoma of the Skin Recurrent Non-Small Cell Lung Carcinoma Recurrent Pancreatic Carcinoma Recurrent Renal Cell Carcinoma Solid Neoplasm Stage IV Breast Cancer Stage IV Non-Small Cell Lung Cancer Stage IV Renal Cell Cancer Stage IV Skin Melanoma Stage IVA Colorectal Cancer Stage IVA Pancreatic Cancer Stage IVB Colorectal Cancer Stage IVB Pancreatic Cancer Collapse <<	Phase 1	Terminated(permanently closed ... more >>per sponsor's request) Collapse <<	-	United States, Arizona ... more >> Mayo Clinic in Arizona Scottsdale, Arizona, United States, 85259 Collapse <<
  NCT02124850	Squamous Cell Carcinoma of the... more >> Head and Neck Collapse <<	Phase 1	Unknown	December 2016	United States, Pennsylvania ... more >> University of Pittsburgh Medical Center Recruiting Pittsburgh, Pennsylvania, United States, 15232 Contact: Carrie Muniz    412-623-6121    munizca@upmc.edu    Principal Investigator: Robert Ferris, MD, PhD Collapse <<
  NCT02431559	Ovarian Cancer	Phase 1 Phase 2	Active, not recruiting	March 2019	United States, Arizona ... more >> Research Facitlity Phoenix, Arizona, United States, 85016 United States, New York Research Facility New York, New York, United States, 10065 United States, Ohio Research Facility Hilliard, Ohio, United States, 43026 United States, Rhode Island Research Facility Providence, Rhode Island, United States, 02905 Switzerland Research Facility Lausanne, Switzerland, 1011 Collapse <<

• 参考文献

• [1] Dietsch GN, Lu H, et al. Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity. PLoS One. 2016 Feb 29;11(2):e0148764.

  [2] Lu H, Dietsch GN, et al. VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC. Clin Cancer Res. 2012 Jan 15;18(2):499-509.

  [3] Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010 May;11(5):373-84.

  [4] Lu H, Dietsch GN, Matthews MA, Yang Y, Ghanekar S, Inokuma M, Suni M, Maino VC, Henderson KE, Howbert JJ, Disis ML, Hershberg RM. VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC. Clin Cancer Res. 2012 Jan 15;18(2):499-509.

  [5] Dietsch GN, Lu H, Yang Y, Morishima C, Chow LQ, Disis ML, Hershberg RM. Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity. PLoS One. 2016 Feb 29;11(2):e0148764.

  [6] Zhang ZJ, Guo JS, Li SS, Wu XB, Cao DL, Jiang BC, Jing PB, Bai XQ, Li CH, Wu ZH, Lu Y, Gao YJ. TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG. J Exp Med. 2018 Dec 3;215(12):3019-3037.

  [7] Dowling DJ, Tan Z, Prokopowicz ZM, Palmer CD, Matthews MA, Dietsch GN, Hershberg RM, Levy O. The ultra-potent and selective TLR8 agonist VTX-294 activates human newborn and adult leukocytes. PLoS One. 2013;8(3):e58164.

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