生物活性

• 描述RAF kinases, consisting of ARAF, BRAF, and CRAF, are key mediators in MAPK signaling cascade. LXH254 is an orally bioavailable inhibitor of both BRAF and CRAF kinases with a high degree of selectivity against a panel of 456 human kinases and in cell-based assays. Due to the capability of inhibiting both RAF monomers and dimers with similar potencies, LXH254 not only blocks MAPK activity in xenograft models harboring BRAF^V600 mutation, but also exhibits inhibitory impact on mutant N- and KRAS-driven signaling^[2]. The IC50 values of LXH254 against BRAF and CRAF are 0.4 and 0.2 nM, respectively. In Calu-6 cells, LXH254 stabilized BRAF-CRAF dimers with an EC50 value of 0.16 µM and inhibited cell proliferation with an EC50 value of 0.28µM. In nude rats bearing Calu-6 human NSCLC xenograft tumors, a single oral dose of LXH254 at 15, 35, 75, and 150 mg/kg reduced pMEK levels in tumors at a dose-dependent manner. Also in Calu-6 xenografts, daily treatment with LXH254 for 18 days showed dose-dependent anti-tumor activity. LXH254 at 15 and 35mg/kg resulted in 29% and 9% T/C, respectively. Administration with 75 mg/kg and 150 mg/kg LXH254 achieved mean tumor regression of 21% and 56%, respectively, compared to vehicle-treated group^[1].

• 动物研究
  剂量	Rat: 15 mg/kg - 150 mg/kg[1] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Mice[1] Rats[1] Dogs[1] Dose 2 mg/kg (i.v.) 4 mg/kg (p.o.) 2 mg/kg (i.v.) 4 mg/kg (p.o.) 0.2 mg/kg (i.v.) 0.4 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. F 65% (p.o.) 38% (p.o.) 79% (p.o.) AUCinf 4.3 μM·h (p.o.) 1.8 μM·h (p.o.) 3.1 μM·h (p.o.) CL 19 ml/min/kg (i.v.) 31 ml/min/kg (i.v.) 3.5 ml/min/kg (i.v.) Cmax 1.6 μM (p.o.) 0.5 μM (p.o.) 0.4 μM (p.o.) Vss 2.1 L/kg (i.v.) 5.4 L/kg (i.v.) 1.7 L/kg (i.v.)

• 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
  NCT03333343	EGFR-mutant Non-small Cell Lun... more >>g Cancer Collapse <<	Phase 1	Recruiting	May 21, 2021	Canada, Ontario ... more >> Novartis Investigative Site Recruiting Toronto, Ontario, Canada, M5G 2M9 Germany Novartis Investigative Site Recruiting Koeln, Germany, 50937 Italy Novartis Investigative Site Recruiting Ancona, AN, Italy, 60126 Novartis Investigative Site Recruiting Milano, MI, Italy, 20162 Singapore Novartis Investigative Site Recruiting Singapore, Singapore, 169610 Taiwan Novartis Investigative Site Recruiting Tainan, Taiwan, 70421 Novartis Investigative Site Recruiting Taipei, Taiwan, 10002 Collapse <<
  NCT02974725	Non-Small Cell Lung Cancer ... more >> Melanoma Collapse <<	Phase 1	Recruiting	June 29, 2020	United States, Massachusetts ... more >> Novartis Investigative Site Recruiting Boston, Massachusetts, United States, 02114 Contact: Bakhan Barzangy    617-726-1849    bbarzangy@mgh.harvard.edu    Principal Investigator: Rebecca Heist          Australia, Victoria Novartis Investigative Site Recruiting Melbourne, Victoria, Australia, 3000 Belgium Novartis Investigative Site Recruiting Leuven, Belgium, 3000 France Novartis Investigative Site Recruiting Villejuif Cedex, France, 94805 Germany Novartis Investigative Site Recruiting Frankfurt, Germany, 60590 Novartis Investigative Site Recruiting Koeln, Germany, 50937 Italy Novartis Investigative Site Recruiting Rozzano, MI, Italy, 20089 Spain Novartis Investigative Site Recruiting Barcelona, Catalunya, Spain, 08036 Collapse <<
  NCT02607813	NSCLC Ovarian... more >> Cancer Melanoma Other Solid Tumors Collapse <<	Phase 1	Recruiting	December 16, 2019	United States, Massachusetts ... more >> Novartis Investigative Site Recruiting Boston, Massachusetts, United States, 02114 United States, New York Novartis Investigative Site Recruiting New York, New York, United States, 10021 Contact: Alida Beck       becka@mskcc.org    Principal Investigator: Gopakumar Iyer          United States, Texas UT M.D Anderson Cancer Center SC - LXH254X2101 Recruiting Houston, Texas, United States, 77030 Contact: Zehra Maloo    713-563-4426    zmaloo@mdanderson.org    Principal Investigator: Filip Janku          Canada, Ontario Novartis Investigative Site Recruiting Toronto, Ontario, Canada, M6G 1Z5 France Novartis Investigative Site Recruiting Paris, France, 75010 Novartis Investigative Site Recruiting Toulouse Cedex 9, France, 31059 Germany Novartis Investigative Site Recruiting Essen, Germany, 45147 Novartis Investigative Site Recruiting Heidelberg, Germany, 69120 Japan Novartis Investigative Site Recruiting Chuo-ku, Tokyo, Japan, 104-0045 Korea, Republic of Novartis Investigative Site Recruiting Seoul, Korea, Korea, Republic of, 03080 Netherlands Novartis Investigative Site Recruiting Groningen, Netherlands, 9713 GZ Contact: Department of Pulmonary Diseases University Medical Center Groningen    +31 503611546    h.j.m.groen@umcg.nl    Principal Investigator: H.J.M. Groen, M.D.          Medical Oncology, Erasmus MC Recruiting Rotterdam, Netherlands, 3075 CE Contact       m.dejonge@erasmusmc.nl    Principal Investigator: M. de Jonge, M.D.          Spain Novartis Investigative Site Recruiting Barcelona, Catalunya, Spain, 08035 Novartis Investigative Site Recruiting Madrid, Spain, 28007 Switzerland Novartis Investigative Site Recruiting Zuerich, Switzerland, 8091 Collapse <<

• 参考文献

• [2] Abstract DDT01-04: Pharmacological profile and anti-tumor properties of LXH254, a highly selective RAF kinase inhibitor