生物活性

• 靶点	ALK IC50:1.6nM

• 描述RTKs (receptor tyrosine kinases) and the RTK signaling pathways play an important role in cellular processes. The oncogenic activation of specific RTKs is the molecular target in advanced non-small cell lung cancer. Entrectinib is a multiple target inhibitor of TrkA, TrkB, TrkC, ROS1 and ALK inhibitor with IC50 values of 1.7, 0.1, 0.1, 0.2 and 1.6nM, respectively. Entrectinib exhibited in vitro anti-proliferative activity with IC50 value of 17nM in KM-12, a human colorectal cancer cell line driven by constitutively active TrkA fusion TPM3-NTRK1, accompanied by inhibition on p-TrkA and the inactivation of its downstream effectors, p-PLCγ1, p-AKT and p-ERK at dose of 10-250nM in 2h, as well as cell cycle arrest and apoptosis. Different manners in oral treatment with Entrectinib, including RXDX-101 at dose 15, 30 and 60mg/kg, BID for 10 days, 15mg/kg BID with 4 days on/ 3 days off for 3 cycles, and 15mg/kg continuously for 3 weeks, resulted in tumor regression and durable stasis in mice bearing KM-12 xenografts, accompanied by sustained intratumoral inhibition of p-TrkA and p-PLCγ1. These suggest that Entrectinib may be a promising therapeutic agent for patients with oncogenic Trk alterations^[1].
• 作用机制Entrectinib is an ATP-competitive inhibitor of the tyrosine kinases TrkA, TrkB, TrkC, ROS1, and ALK.^[1]

• 动物研究
  剂量	Mice: 60 mg/kg, 120 mg/kg[4] (p.o.) Nude Mice[2] (p.o.): 60 mg/kg (BID)
  给药途径	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
  NCT03178552	Non-Small Cell Lung Cancer	Phase 2 Phase 3	Recruiting	January 2, 2022	-
  NCT03375437	Soft Tissue Sarcoma ... more >> Advanced Cancer Metastatic Cancer Collapse <<	Not Applicable	Recruiting	January 15, 2021	France ... more >> Centre Georges-Francois Leclerc Recruiting Dijon, France, 21079 Contact: Nicolas ISAMBERT, MD       nisambert@cgfl.fr    Sub-Investigator: Céline CHARON BARRA, MD          Sub-Investigator: Audrey HENNEQUIN, MD          Sub-Investigator: Alice HERVIEU, MD          Sub-Investigator: Sylvie ZANETTA, MD          Centre Oscar Lambret Recruiting Lille, France, 59000 Contact: Nicolas PENEL, MD          Principal Investigator: Nicolas PENEL, MD          Sub-Investigator: Fredrik LAESTADIUS, MD          Sub-Investigator: Diane PANNIER, MD          Sub-Investigator: Yves-Marie ROBIN, MD          Sub-Investigator: Thomas RYCKEWAERT, MD          CHU de Limoges Hôpital Dupuytren Recruiting Limoges, France Contact: Valérie LEBRUN-LY, MD          Principal Investigator: Valérie LEBRUN-LY, MD          Sub-Investigator: Sandrine LAVAU-DENES, MD          Sub-Investigator: Isabelle POMMEPUY, MD          Centre Léon Bérard Recruiting Lyon, France, 69008 Contact: Armelle DUFRESNE, MD          Sub-Investigator: Jean-Yves BLAY, MD          Sub-Investigator: Mehdi BRAHMI, MD          Sub-Investigator: Philippe CASSIER, MD          Sub-Investigator: Nadège CORRADINI, MD          Sub-Investigator: Isabelle RAY-COQUARD, MD          Institut de Cancérologie de la Loire Lucien Neuwirth Recruiting Saint-Priest-en-Jarez, France Contact: Olivier COLLARD, MD       olivier.collard@icloire.fr    Principal Investigator: Olivier COLLARD, MD Collapse <<
  NCT02650401	Solid Tumors ... more >>CNS Tumors Neuroblastoma Collapse <<	Phase 1	Recruiting	December 31, 2022	-

• 更多
• 参考文献

• [1] D. Anderson, M. Ciomei, et al. Inhibition of Trk-driven tumors by the pan-Trk inhibitor RXDX-101. ejcancer. Volume 50, Supplement 6, Page 101.

  [2] Iyer R, Wehrmann L, et al. Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model. Cancer Lett. 2016;372(2):179-86.

  [3] Ardini E, Menichincheri M, et al. Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. Mol Cancer Ther. 2016;15(4):628-39.

  [4] Entrectinib for the Treatment of Pediatric Cancers Harboring an Activating Alteration of NTRK1/2/3, ROS1, or ALK