生物活性

• 描述Savolitinib is a novel triazolopyrazine-based c-Met inhibitor with IC50 values of 5nM, 3nM and 6nM for inhibition of c-Met enzyme, HGF-mediated c-Met phosphorylation and HGF-induced proliferation assay in NCI-H441 cell line, respectively. Single oral dose of 3 mg/kg Savolitinib achieved inhibition of HGF-mediated c-Met phosphorylation by 84.7% at 6h post administration in mice. Oral dose of savolitinib at 1, 2.5 and 10mg/kg once daily for 21 days dose-dependently inhibited tumor growth in U87MG subcutaneous xenograft athymic nude mice model^[1]. The MET D1228 site is important for Savolitinib, for the MET D1228V mutation could induce resistance to type I MET inhibitor like savolitinib^[2].
• 作用机制Savolitinib can bind to c-Met in a unique mode including wrapping around Met1211 c-Met in a“U-shaped” conformation. It also binds to the activation loop through Asp1228 and Lys1110 residues.^[1][2]

• 动物研究
  剂量	Mice: 0.3 mg/kg - 10 mg/kg[3] (p.o.), 50 mg/kg[4] (p.o.); 0.6 mg/kg[3] (i.v.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Mice[1] Dose 2.5 mg/kg (i.v.) 10 mg/kg (p.o.) Administration i.v. p.o. F 27.2% (p.o.) T1/2 1.7 h (p.o.) Vz 1.2 l/kg (i.v.) CLp 0.66 l/h·kg (i.v.) Cmax 4947 ng/ml (p.o.) AUC0→8h 5594 ng·h/ml (p.o.)

• 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
  NCT02143466	Advanced Non Small Cell Lung C... more >>ancer Collapse <<	Phase 1	Recruiting	December 30, 2019	-
  NCT03385655	Prostate Cancer	Phase 2	Recruiting	December 31, 2020	Canada, Alberta ... more >> Cross Cancer Institute Recruiting Edmonton, Alberta, Canada, T6G 1Z2 Contact: Michael Kolinsky    780 432-8762       Canada, British Columbia BCCA - Vancouver Cancer Centre Recruiting Vancouver, British Columbia, Canada, V5Z 4E6 Contact: Kim Chi    604 877-6000 ext 2746       Canada, Nova Scotia QEII Health Sciences Centre Recruiting Halifax, Nova Scotia, Canada, B3H 1V7 Contact: Robyn J. Macfarlane    902 473-6106       Canada, Ontario Juravinski Cancer Centre at Hamilton Health Sciences Recruiting Hamilton, Ontario, Canada, L8V 5C2 Contact: Som Mukherjee    905 387-9495 ext 64605       London Regional Cancer Program Recruiting London, Ontario, Canada, N6A 5W9 Contact: Eric W. Winquist    519 685-8261       Ottawa Hospital Research Institute Recruiting Ottawa, Ontario, Canada, K1H 8L6 Contact: Michael Ong    613 737-7700 ext 75051       University Health Network Recruiting Toronto, Ontario, Canada, M5G 2M9 Contact: Adrian Sacher    416 946-4501 ext 3550       Canada, Quebec CHUM-Centre Hospitalier de l'Universite de Montreal Recruiting Montreal, Quebec, Canada, H2X 3E4 Contact: Fred Saad    514 890-8000 ext 27466       The Jewish General Hospital Recruiting Montreal, Quebec, Canada, H3T 1E2 Contact: Cristiano Ferrario    514 398-8307       Canada, Saskatchewan Allan Blair Cancer Centre Recruiting Regina, Saskatchewan, Canada, S4T 7T1 Contact: Muhammad Salim    306 766-2691       Saskatoon Cancer Centre Recruiting Saskatoon, Saskatchewan, Canada, S7N 4H4 Contact: Nayyer Iqbal    306 655-2710 Collapse <<
  NCT02447380	Advanced Gastric Adenocarcinom... more >>a Collapse <<	Phase 2	Recruiting	December 2019	Korea, Republic of ... more >> Samsung Medical Center Recruiting Seoul, Seoul, Korea, Republic Of, Korea, Republic of, 135-710 Contact: yoon Jeong Ahn    221487395 ext 82       Principal Investigator: Seung Tae Kim, M.D., Ph.D. Collapse <<

• 更多
• 参考文献

• [1] Jia H, Dai G, et al. Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (volitinib) as a highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitor in clinical development for treatment of cancer. J Med Chem. 2014 Sep 25;57(18):7577-89.

  [2] Bahcall M, Sim T, et al. Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer. Cancer Discov. 2016 Dec;6(12):1334-1341. Epub 2016 Sep 30.

  [3] Gavine PR, Ren Y, et al. Volitinib, a potent and highly selective c-Met inhibitor, effectively blocks c-Met signaling and growth in c-MET amplified gastric cancer patient-derived tumor xenograft models. Mol Oncol. 2015 Jan;9(1):323-33.

  [4] Henry RE, Barry ER, et al. Acquired savolitinib resistance in non-small cell lung cancer arises via multiple mechanisms that converge on MET-independent mTOR and MYC activation. Oncotarget. 2016 Sep 6;7(36):57651-57670.