生物活性

• 靶点

  c-FMS IC50:20nM

  c-Kit IC50:10nM

  FLT3 IC50:160nM

• 描述The inhibition of CSF-1R, which can deplete macrophages and reduce tumor volume, is an effective strategy to treat for glioblastoma multiforme because of the crucial function of CSF-1R through the paracrine CSF-1–EGF signaling loop in glioma microenvironment forming by the tumor-associated macrophages and microglia (TAMs). Pexidartinib is a muti-target inhibitor with IC50 values of 10nM, 20nM and 160nM for c-kit and CSF-1R (measured by in vitro kinase assays), 10- to 100-fold selectivity against other 226 different kinases tested. Inhibition of CSF-1R by Pexidartinib could alter tumor immune microenvironment in vivo thus significantly decreasing primary tumor progression and enhancing the common cytotoxic drugs, like paclitaxel, in breast cancer. Instead of altering TAMs maturation of differentiation, treatment with Pexidartinib significantly inhibited both steady-state and paclitaxel-induced infiltration by TAMs in late-stage MMTV-PyMT mice. Combined paclitaxel therapy with CSF1-signaling blockade by Pexidartinib can foster an antitumor immune response by increased T lymphocytes (CD4+ and CD8+ T cells) with high expression of cytotoxic effector molecules, such as IFN-, granzyme A, granzyme B, perforin-1, the type 1 DC effector molecules, IL12p35 and IFN-α, in mammary tumors, which may due to the macrophage depletion. Thus this facilitate the enhanced cytotoxic response and block of metastasis, both of which were CD8+ T-cell-dependent. Oral treatment with 40mg/kg Pexidartinib for 5 days, followed with 10 mg/kg paclitaxel, i.v., for 4 cycles, caused reduce of primary tumor burden in MMTV-PyMT mice^[1].
• 作用机制Pexidartinib is a competitive ATP inhibitor.^[1]

• 动物研究
  剂量	Mice: 10 mg/kg, 50 mg/kg[2] (p.o.), 0.25 mg/kg - 1 mg/kg[3] (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
  NCT01525602	Solid Tumors	Phase 1	Completed	-	United States, Alabama ... more >> University of Alabama at Birmingham Birmingham, Alabama, United States, 35233 United States, California Univeristy of California, San Francisco San Francisco, California, United States, 94143 United States, Colorado University of Colorado, Anschutz Cancer Pavilion Aurora, Colorado, United States, 80045 United States, Florida Sylvester Comprehensive Cancer Center/UMHC Miami, Florida, United States, 33136 United States, Minnesota Mayo Clinic Rochester, Minnesota, United States, 55905 United States, Ohio University Hospitals of Cleveland Cleveland, Ohio, United States, 44106 Ohio State University Columbus, Ohio, United States, 43210 United States, Utah University of Utah, Huntsman Cancer Institute Salt Lake City, Utah, United States, 84112 Collapse <<
  NCT02975700	Melanoma	Not Applicable	Active, not recruiting	February 2020	China, Beijing ... more >> Beijing Cancer Hospital Beijing, Beijing, China, 100142 China, Guangdong Sun Yat-sen Hospital Guangzhou, Guangdong, China Korea, Republic of Samsung Medical Center Gangnam-gu, Seoul, Korea, Republic of, 06351 Severance Hospital, Yonsei University Health System Seodaemun-gu, Seoul, Korea, Republic of, 03722 Seoul National University Hospital Seoul, Korea, Republic of Collapse <<
  NCT02371369	Pigmented Villonodular Synovit... more >>is Giant Cell Tumors of the Tendon Sheath Tenosynovial Giant Cell Tumor Collapse <<	Phase 3	Active, not recruiting	December 2018	-

• 更多
• 参考文献

• [1] DeNardo DG, Brennan DJ, Rexhepaj E, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011;1(1):54-67