生物活性

• 靶点

  ALK IC50:1.01nM

  ALK (L1196M) IC50:1.08nM

  ALK (G1202R) IC50:1.26nM

  Src IC50:5.3nM

• 描述TPX-0005 is a potent ATP-competitive multiple-target inhibitor against ALK, ROS1, TRKA, TRKB and TRKC recombinant kinases and their corresponding clinical resistant mutants, as well as SRC, with IC50 values of 1.01nM, 1.26nM, 1.08nM and 5.3nM for WT ALK, ALK^G1202R, ALK^L1196M and SRC, respectively. Compared with the current ALK inhibitors, TPX-0005 possesses a novel three-dimensional macrocycle with a much smaller size. TPX-0005 exhibited potent anti-proliferative activity against a number of cell lines with IC50 values of subnanomolar or nanomolar, accompanied by inhibition of target phosphorylation and concomitant inactivation of downstream effectors such as ERK, AKT and STAT3. Treatment with TPX-0005 resulted in significant regression of tumors harboring the oncogenic ALK, ROS1 and TRKC fusions of patient derived xenograft tumor models^[1][2]. Oral administration of TPX-0005, twice daily, led tumor growth inhibition of 197% and 200% against CD74–ROS1 WT tumors and 99% and 200% against CD74–ROS1^G2032R tumors, at dose of 15 or 75mg/kg (crystalline form), respectively, in SCID/Beige mice. Also, when dosed in a micronized crystalline formulation, TPX-0005 resulted in tumor growth inhibition of 100% and 128% against NIH3T3 LMNA–TRKA WT tumors at dose of 3 and 15 mg/kg, respectively, as well as 56%, 97% and 123% against TRKA^G595R tumors at dose of 3, 15, or 60 mg/kg in athymic nude mice. This TGI by TPX-0005 could also be observed in SCID/Beige mice bearing Ba/F3 EML4–ALK v1 WT or EML4–ALK v1 ^G1202R xenograft tumors at dose of 15 or 75 mg/kg^[3].
• 作用机制TPX-0005 is an ATP-competitive inhibitor designed to efficiently target the center of the ATP binding site and circumvent the steric interference from mutations outside the ATP binding boundary.^[1]

• 动物研究
  剂量	Mice[3] (p.o.): 15 mg/kg, 75 mg/kg (b.i.d.)
  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
  NCT03093116	Locally Advanced Solid Tumors ... more >> Metastatic Solid Tumors Non Hodgkin Lymphoma Collapse <<	Phase 1 Phase 2	Recruiting	December 2021	United States, California ... more >> UC Irvine Health, Chao Family Comprehensive Cancer Center Recruiting Orange, California, United States, 92868 Contact: Susanna Searcy    877-827-8839    ucstudy@uci.edu    United States, Colorado University of Colorado Denver Recruiting Aurora, Colorado, United States, 80045 Contact: Paula Fisk    720-848-0676    paula.fisk@ucdenver.edu    United States, Massachusetts Massachusetts General Hospital Recruiting Boston, Massachusetts, United States, 02114 Contact: Alice T Shaw, M.D., Ph.D.    617-724-4000    ashaw1@partners.org    United States, New York Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States, 10065 Contact: Deepa Ramaswami    646-888-4425    ramaswad@mskcc.org    Contact: Judy Nguyen    (646) 888-4425    Nguyenj2@mskcc.org    Korea, Republic of Seoul National University Hospital Recruiting Seoul, Korea, Republic of, 110-744 Contact: Dong-Wan Kim, M.D., Ph.D.    +82-2-2072-2995    kimdw@snu.ac.kr    Yonsei Cancer Center, Severance Hospital Recruiting Seoul, Korea, Republic of, 120-752 Contact: Byoung Chul Cho, M.D., Ph.D.    +82-2-2228-8126    cbc1971@yuhs.ac    Samsung Medical Center Recruiting Seoul, Korea, Republic of, 135-710 Contact: Jeeyun Lee, M.D., Ph.D.    +82-2-3410-3459    jyun.lee@samsung.com Collapse <<

• 参考文献

• [1] Abstract 3168: Overcoming acquired drug resistance by TPX-0005, an ALK, ROS1 and pan-TRK inhibitor

  [2] Abstract 2132: The novel, rationally-designed, ALK/SRC inhibitor TPX-0005 overcomes multiple acquired resistance mechanisms to current ALK inhibitors

  [3] Drilon A, Ou SI, Cho BC, et al. Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. Cancer Discov. 2018;8(10):1227-1236