生物活性

• 靶点	B-Raf (V600E) IC50:~5nM

• 描述PLX8394 is a new generation of BRAF inhibitor with IC50 of appr 5nM for BRAF^V600E. Unlike the first-generation inhibitors like vemurafenib and dabrafenib, PLX8394 can blocks signaling from both monomeric BRAF^V600E and dimeric BRAFnon-V600 mutations without paradoxical effects in wild-type cells.PLX8394 at concentration ranging in 0.1-30μM led a concentration-dependent decrease of p-MEK1/2 and p-ERK1/2 in both SK-MEL-239 cells with BRAF^V600E monomers and SK-MEL-239 C4 cells with p61 BRAF^V600E homodimers post 1 hour treatment, and almost did not affect the level of p-MEK1/2 or p-ERK1/2 in SK-MEL-2 cells with WT RAF dimers. PLX8394 could inhibit ERK signaling by specifically disrupting BRAF-containing dimers, but not CRAF homodimers or ARAF-containing dimers. Thus, it inhibited ERK signaling driven by BRAF monomers or dimers but activated ERK signaling driven by CRAF homodimers. Administration of 50mg/kg PLX8394 twice daily in nude mice preferentially inhibited ERK signaling and tumor growth driven by RAS-independent BRAF mutants (BRAF V600E amp) .

• 动物研究
  剂量	Mice: 50 mg/kg[3] (i.p., BID)
  给药途径	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
  NCT02428712	Advanced Unresectable Solid Tu... more >>mors BRAF-mutated Tumors Collapse <<	Phase 1 Phase 2	Active, not recruiting	April 2020	United States, Arizona ... more >> HonorHealth Scottsdale, Arizona, United States, 85258 United States, California University of California, San Francisco San Francisco, California, United States, 94143 Stanford Hospitals and Clinics Stanford, California, United States, 94305 United States, Florida University of Miami Miami, Florida, United States, 33136 United States, Massachusetts Massachusetts General Hospital Boston, Massachusetts, United States, 02114 Beth Israel Deaconess Medical Center Boston, Massachusetts, United States, 02215 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, Pennsylvania Thomas Jefferson University Medical Oncology Clinica Philadelphia, Pennsylvania, United States, 19107 United States, Tennessee Vanderbilt University Nashville, Tennessee, United States, 37232 United States, Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Texas Children's Hospital (Baylor College of Medicine) Houston, Texas, United States, 77030 United States, Utah Huntsman Cancer Institute Salt Lake City, Utah, United States, 84112 Collapse <<
  NCT02012231	Melanoma Thyr... more >>oid Cancer Colorectal Cancer Non-small Cell Lung Cancer Cholangiocarcinoma Histiocytosis Hairy Cell Leukemia Collapse <<	Phase 1 Phase 2	Terminated	-	United States, Arizona ... more >> Scottsdale Healthcare Scottsdale, Arizona, United States, 85258 United States, Utah Huntsman Cancer Institute Salt Lake City, Utah, United States, 84112 United States, Washington Evergreen Hematology & Oncology Spokane, Washington, United States, 99218 Collapse <<

• 参考文献

• [1] Okimoto RA, Lin L, et al. Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF-mutant lung cancer. Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):13456-13461.

  [2] Basile KJ, Le K, et al. Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors. Pigment Cell Melanoma Res. 2014 May;27(3):479-84.