生物活性

• 靶点	Axl IC50:27nM

• 描述Axl belongs to the TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases (RTK). The extracellular portion of AXL has properties and structural elements similar to cell adhesion molecules that may participate in cell-to-cell contacts that are not fully understood. In addition to this, AXL binds to the soluble ligand of GAS6 (growth arrest-specific 6) that activates downstream signaling networks responsible for its biological effects. GAS6 binding to AXL results in receptor dimerization and AXL autophosphorylation. This activation results in downstream signaling to the PI3K/AKT, MAPK, and NF-κB pathways. TP-0903 is an Axl kinase inhibitor with IC₅₀ of 27 nM. TP-0903 was active in cell viability assays with an IC₅₀ of 6 nM against the pancreatic cancer cell line PSN-1. PSN-1 cells were stimulated with GAS6 in the presence of the concentrations of 0.03, 0.1, 0.3, 1, 3 or 10 μM of TP-0903. TP-0903 concentration-dependently suppressed phospho-AKT and phospho-AXL levels with EC₅₀s of 305 and 222 nM, respectively^[3]. Tumor cells derived from chronic lymphocytic leukemia (CLL) patients were treated by 0.1 μM of TP-0903 and the results were that TP-0903 induced PARP cleavage and caspase-3 activation in 3 of 4 patient samples. In another assay, purified CLL B cells sensitive to TP-0903 were cultured alone or cocultured with CLL BMSCs from 3 different CLL patients followed by treatment with 0.1 mM or 0.175 mM of TP-0903 for 24 h. It was suggested that TP-0903 overcomes CLL BMSC-mediated protection of CLL B cells from apoptosis^[4].
• 作用机制TP-0903 is an Axl kinase inhibitor. Structural study suggested that TP-0903 interacted with the ATP binding site of Axl kinase. In detail, the pyrimidine nitrogen of TP-0903 was involved in a hydrogen-binding interaction with the Met623 residue in the hinge region of the kinase^[3].
• 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
  NCT02729298	Advanced Solid Tumors ... more >> EGFR Positive Non-small Cell Lung Cancer Colorectal Carcinoma Recurrent Ovarian Carcinoma BRAF-Mutated Melanoma Collapse <<	Phase 1	Recruiting	September 2019	United States, Arizona ... more >> Mayo Clinic Arizona Recruiting Phoenix, Arizona, United States, 85054 Contact: Debbie Gallagher, RN       gallagher.deborah@mayo.edu    Principal Investigator: Mahesh Seetharam, MD          HonorHealth Research Institute Recruiting Scottsdale, Arizona, United States, 85258 Contact: Joyce Schaffer, RN    480-323-1339    clinicaltrials@honorhealth.com    Principal Investigator: Vivek Khemka, MD          United States, Florida Mayo Clinic Florida Recruiting Jacksonville, Florida, United States, 32224 Contact: Torsak Vimoktayon, MPH       vimoktayon.torsak@mayo.edu    Principal Investigator: YanYan Lou, MD          United States, Minnesota Mayo Clinic Rochester Recruiting Rochester, Minnesota, United States, 55905 Contact: Danielle Sommerfeldt       sommerfeldt.danielle@mayo.edu    Principal Investigator: Alex Adjei, MD          United States, Texas University of Texas Southwestern Medical Center Recruiting Dallas, Texas, United States, 75390 Contact: Yolanda Pitts       yolanda.pitts@utsouthwestern.edu    Principal Investigator: Muhammad Beg, MD          University of Texas Science Center at San Antonio (UTHSCSA) Recruiting San Antonio, Texas, United States, 78229 Contact: CTRC    210-450-2872       Principal Investigator: John Sarantopoulos, MD Collapse <<
  NCT03572634	Chronic Lymphocytic Leukemia ... more >> CLL SLL Small Lymphocytic Lymphoma Collapse <<	Phase 1 Phase 2	Not yet recruiting	April 2021	United States, Minnesota ... more >> Mayo Clinic Not yet recruiting Rochester, Minnesota, United States, 55905 Contact: Neil Kay, MD          Principal Investigator: Neil Kay, MD Collapse <<

• 参考文献

• [1] Sinha S, Boysen J, et al. Targeted Axl Inhibition Primes Chronic Lymphocytic Leukemia B Cells to Apoptosis and Shows Synergistic/Additive Effects in Combination with BTK Inhibitors. Clin Cancer Res. 2015 May 1;21(9):2115-26.

  [2] Mollard A, Warner SL, et al. Design, Synthesis and Biological Evaluation of a Series of Novel Axl Kinase Inhibitors. ACS Med Chem Lett. 2011 Dec 8;2(12):907-912.

  [3] Mollard A, Warner SL, Call LT, Wade ML, Bearss JJ, Verma A, Sharma S, Vankayalapati H, Bearss DJ. Design, Synthesis and Biological Evaluation of a Series of Novel Axl Kinase Inhibitors. ACS Med Chem Lett. 2011 Dec 8;2(12):907-912.

  [4] Sinha S, Boysen J, Nelson M, Secreto C, Warner SL, Bearss DJ, Lesnick C, Shanafelt TD, Kay NE, Ghosh AK. Targeted Axl Inhibition Primes Chronic Lymphocytic Leukemia B Cells to Apoptosis and Shows Synergistic/Additive Effects in Combination with BTK Inhibitors. Clin Cancer Res. 2015 May 1;21(9):2115-26.