生物活性

• 描述Mitogen-activated protein kinase interacting kinases (MNK) 1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. eFT508 Is a potent Inhibitor of MNK1 and MNK2 signaling and tumor growth. In all cell lines tested, eFT508 inhibited Ser209 phosphorylation of eIF4E with IC₅₀ values ranging from 1.4 to 22 nM. This effect of eFT508 on eIF4E Ser209 phosphorylation is specific to MNK1/2 inhibition. Treatment of TMD8 cells for 48 h with eFT508 led to a dose-dependent reduction in secreted IL-6, IL-8, and TNFα. Taken together, eFT508 potently inhibited eIF4E phosphorylation, select mRNA stability, and pro-inflammatory cytokineproduction in DLBCL cells. eFT508 was well-tolerated at doses of 1 and 10 mg/kg QD as measured by lack of body weight loss, which corresponds to aminimal therapeutic index of≥10 in a TMD8 xenograft model. Furthermore, eFT508 treatment produced significant tumor growth inhibition (TGI) over a 10-fold dose range, achieving an average TGI of 71% and 75% when dosed orally at 1 and 10 mg/kg QD, respectively^[2].
• 作用机制eFT508 makes H-bond interactions with both hinge residues, Lys161 and Met162. The pyridone methyl interacts with the face of Phe159, and the Cys225 sulfur makes a Dunitz interaction^[2].
• 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
  NCT03616834	Solid Tumors	Phase 2	Recruiting	December 2019	United States, California ... more >> Pacific Shores Medical Group Recruiting Long Beach, California, United States, 90813 Contact: Irene De Jesus    562-590-0345    irened@pacshoresoncology.com    Principal Investigator: Nishan Tchekmedyian, MD          St. Joseph Heritage Healthcare Recruiting Santa Rosa, California, United States, 95403 Contact: Camille Shaffer    707-521-3809    camille.shaffer@stjoe.org    Principal Investigator: Thomas Stanton, MD          United States, Georgia Columbus Regional Research Institute Recruiting Columbus, Georgia, United States, 31904 Contact: Courtney Alexander    706-660-6449    calexander@iacthealth.com    Principal Investigator: Andrew Pippas, MD          United States, Idaho Saint Alphonsus Regional Medical Center Recruiting Boise, Idaho, United States, 83706 Contact: Olga Bittner       olga.bittner@saintalphonsus.org    Principal Investigator: Kerry Pulver, MD, PhD          United States, Indiana Indiana University Health Melvin & Bren Simon Cancer Center Recruiting Indianapolis, Indiana, United States, 46202 Contact: Suzanne Bailey    317-278-4694    subailey@iupui.edu    Principal Investigator: Bert O'Neil, MD          United States, Maryland Anne Arundel Medical Center Recruiting Annapolis, Maryland, United States, 21401 Contact: Steven DeMartino    443-481-4390    sdemartino@aahs.org    Principal Investigator: Peter Graze, MD          United States, Michigan Karmanos Cancer Institute Recruiting Detroit, Michigan, United States, 48201 Contact: Sarah Chalabi    313-576-8993    chalabis@karmanos.org    Principal Investigator: Amy Weise, DO          United States, Ohio Universty of Toledo Medical Center Recruiting Toledo, Ohio, United States, 43614 Contact: Stephanie Smiddy    419-383-6962    stephanie.smiddy@utoledo.edu    Principal Investigator: John Nemunaitis          United States, Oregon Providence Portland Medical Center Recruiting Portland, Oregon, United States, 97213 Contact: Melissa Pomeroy    503-215-2714    melissa.pomeroy@providence.org    Principal Investigator: Rachel Sanborn, MD          United States, South Carolina Spartanburg Medical Center Recruiting Spartanburg, South Carolina, United States, 29303 Contact: Ken Kuenzli    864-560-6812    kkuenzli@gibbscc.org    Principal Investigator: Vikas Demblas, MD          United States, South Dakota Avera Cancer Institute Recruiting Sioux Falls, South Dakota, United States, 57105 Contact: Karin Swenson    605-322-3018    karin.swenson@avera.org    Principal Investigator: Benjamin Solomon, MD          United States, Virginia Virginia Cancer Specialists, PC Recruiting Fairfax, Virginia, United States, 22031 Contact: Claudia Phillips    703-208-9268    claudia.phillips@usoncology.com    Principal Investigator: Alexander Spira, MD          United States, Wisconsin University of Wisconsin Clinical Science Center Recruiting Madison, Wisconsin, United States, 53792 Contact: Jennifer Collins    608-265-0811    jennifer.collins@wisc.edu    Principal Investigator: Nataliya Uboha, MD, PhD Collapse <<
  NCT02937675	Lymphoma	Phase 1 Phase 2	Terminated(patient recruitment... more >>) Collapse <<	-	United States, California ... more >> Samuel Oschin comprehensive Cancer Institute at Cedars-Sinai Medical Center Los Angeles, California, United States, 90048 United States, Florida Florida Cancer Specialist Sarasota, Florida, United States, 34232 United States, Michigan Karmanos Cancer Institute Detroit, Michigan, United States, 48201 Henry Ford Hospital Detroit, Michigan, United States, 48202 United States, Minnesota Mayo Clinic Rochester, Minnesota, United States, 55905 United States, New York University of Rochester Rochester, New York, United States, 14642 United States, Ohio Gabrail Cancer Center Research Canton, Ohio, United States, 44718 United States, Texas Baylor Scott & White Research Institute Dallas, Texas, United States, 75246 United States, Washington Seattle Cancer Care Alliance Seattle, Washington, United States, 98109 United States, West Virginia West Virginia University Morgantown, West Virginia, United States, 26506 Collapse <<
  NCT02605083	Cancer	Phase 1 Phase 2	Terminated(The study was termi... more >>nated after determination of the RP2D, prior to opening expansion cohorts)) Collapse <<	-	United States, Colorado ... more >> SCRI at HealthONE Denver, Colorado, United States, 80218 United States, Florida Florida Cancer Specialists Sarasota, Florida, United States, 34232 United States, Tennessee Tennessee Oncology, PLLC Nashville, Tennessee, United States, 37203 United States, Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<

• 更多
• 参考文献

• [1] Kevin R, Vikas K, eFT508, a Potent and Selective Mitogen-Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 Inhibitor, Is Efficacious in Preclinical Models of Diffuse Large B-Cell Lymphoma (DLBCL). Blood 2015 126:1554

  [2] Reich SH, Sprengeler PA, Chiang GG, et al. Structure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition. J Med Chem. 2018;61(8):3516-3540.