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, ALKG1202R, ALKL1196M 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–ROS1G2032R 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 TRKAG595R 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]
Repotrectinib/瑞普替尼 细胞实验
Cell Line
Concentration
Treated Time
Description
References
KM12SM cells
1 μM
72 h
KM12SM cells were sensitive to repotrectinib, IC50 of 1.2 nM
Cancer Sci. 2022 Jul;113(7):2323-2335.
IRC and KM12 cells
1-5000 nM
72 hours
To assess the effect of Selpercatinib on the growth inhibition and TRK-mediated signaling in NTRK fusion-positive tumor cells. Results showed that Selpercatinib significantly inhibited tumor cell growth and TRK signaling.
Br J Cancer. 2024 Aug;131(3):601-610.
Ba/F3_G595R cells
1 μM
72 h
Ba/F3_G595R cells were sensitive to repotrectinib
Cancer Sci. 2022 Jul;113(7):2323-2335.
Ba/F3_WT cells
1 μM
72 h
Ba/F3_WT cells were sensitive to repotrectinib
Cancer Sci. 2022 Jul;113(7):2323-2335.
M3B cells
1 μM
72 h
M3B cells were resistant to repotrectinib, IC50 of 295.7 nM
Cancer Sci. 2022 Jul;113(7):2323-2335.
YU1079
0.097 μM
72 h
To evaluate the anti-tumor activity of Repotrectinib in crizotinib-resistant ROS1 G2032R mutation models, results showed that Repotrectinib significantly inhibited the growth of YU1079 cells.
Clin Cancer Res. 2020 Jul 1;26(13):3287-3295.
YU1078
0.021 µM
72 h
To evaluate the anti-tumor activity of Repotrectinib in treatment-naïve ROS1-rearranged NSCLC models, results showed that Repotrectinib significantly inhibited the growth of YU1078 cells.
Clin Cancer Res. 2020 Jul 1;26(13):3287-3295.
SK-N-BE
510.8 ± 16.94 nM
5 days
Repotrectinib has a weaker inhibitory effect on the proliferation of non-ALK-addicted neuroblastoma cells SK-N-BE.
Sci Rep. 2019 Dec 18;9(1):19353.
SK-N-AS
594.8 ± 47.3 nM
5 days
Repotrectinib has a weaker inhibitory effect on the proliferation of non-ALK-addicted neuroblastoma cells SK-N-AS.
Sci Rep. 2019 Dec 18;9(1):19353.
Kelly
310.9 ± 7.9 nM
5 days
Repotrectinib inhibits proliferation of ALK-addicted neuroblastoma cells and reduces phosphorylation levels of pY1604-ALK, pERK5, pSTAT3, p-p70 S6K, pAKT, and pERK.
Sci Rep. 2019 Dec 18;9(1):19353.
CLB-GE
259.4 ± 6.3 nM
5 days
Repotrectinib inhibits proliferation of ALK-addicted neuroblastoma cells and reduces phosphorylation levels of pY1604-ALK, pERK5, pSTAT3, p-p70 S6K, pAKT, and pERK.
Sci Rep. 2019 Dec 18;9(1):19353.
CLB-BAR
124.1 ± 4.89 nM
5 days
Repotrectinib inhibits proliferation of ALK-addicted neuroblastoma cells and reduces phosphorylation levels of pY1604-ALK, pERK5, pSTAT3, p-p70 S6K, pAKT, and pERK.
Sci Rep. 2019 Dec 18;9(1):19353.
NIH-3T3-tv-a cells
100 nM
5 days
To evaluate the growth inhibitory effect of Repotrectinib on TPM3-NTRK1-G595R mutant spheroids, results showed that Repotrectinib significantly inhibited the growth of mutant spheroids.
Cell Rep. 2024 Oct 22;43(10):114829.
NIH-3T3-tv-a cells
100 nM
5 days
To evaluate the growth inhibitory effect of Repotrectinib on TPM3-NTRK1-F589L mutant spheroids, results showed that Repotrectinib significantly inhibited the growth of mutant spheroids.
Cell Rep. 2024 Oct 22;43(10):114829.
NIH-3T3-tv-a cells
100 nM
5 days
To evaluate the growth inhibitory effect of Repotrectinib on NTRK fusion-driven spheroids, results showed that Repotrectinib significantly inhibited the growth of spheroids.
Cell Rep. 2024 Oct 22;43(10):114829.
KM12 cells
<0.03 nM
4 h
Repotrectinib was the most potent inhibitor of TRKA autophosphorylation, with an IC50 value less than 0.03 nM.
Mol Cancer Ther. 2021 Dec;20(12):2446-2456.
Ba/F3 cells
<0.2 nM
72 h
Repotrectinib showed the highest potency against wild-type TRKA, TRKB, and TRKC fusions, with IC50 values less than 0.2 nM.
Mol Cancer Ther. 2021 Dec;20(12):2446-2456.
HCC78 ROS1L2026M
1 - 5000 nM
120 h
To evaluate the inhibitory effect of Repotrectinib on ROS1L2026M mutant cells, results showed significant resistance of ROS1L2026M cells to Repotrectinib
J Transl Med. 2024 Mar 3;22(1):234.
HCC78 ROS1G2032R
1 - 5000 nM
120 h
To evaluate the inhibitory effect of Repotrectinib on ROS1G2032R mutant cells, results showed significant resistance of ROS1G2032R cells to Repotrectinib
J Transl Med. 2024 Mar 3;22(1):234.
Repotrectinib/瑞普替尼 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
YU1078 xenograft model
Oral
15 mg/kg
Twice daily, for 21 days
To evaluate the anti-tumor activity of Repotrectinib in the YU1078 xenograft model, results showed that Repotrectinib significantly inhibited tumor growth and delayed tumor recurrence.
Clin Cancer Res. 2020 Jul 1;26(13):3287-3295.
Mice
Neuroblastoma xenograft model
Oral
20 mg/kg, twice daily
Twice daily for 14 days
Repotrectinib significantly inhibits tumor growth in a neuroblastoma xenograft model, with a tumor growth inhibition (TGI) of 87.07%, and animals gained weight.
Sci Rep. 2019 Dec 18;9(1):19353.
Mice
NTRK fusion-driven glioma models
Intraperitoneal (i.p.) injection
20 mg/kg
Twice a day for 25 hours
To evaluate the therapeutic effect of Repotrectinib on NTRK fusion-driven gliomas, results showed that Repotrectinib significantly reduced p-ERK and p-S6 levels in tumor tissue and induced apoptosis.
Cell Rep. 2024 Oct 22;43(10):114829.
Nude mice
NIH3T3 LMNA–TRKA xenograft model
Oral
3 mg/kg, 10 mg/kg, 30 mg/kg
Twice daily, continuous treatment
Repotrectinib demonstrated significant antitumor activity in the LMNA–TRKAG595R xenograft model, achieving 95% tumor growth inhibition, 19% tumor regression, and 46% tumor regression at doses of 3 mg/kg, 10 mg/kg, and 30 mg/kg, respectively.
Mol Cancer Ther. 2021 Dec;20(12):2446-2456.
SHO mice
Brain metastasis model
Oral
15 mg/kg
Daily, continuous treatment
Single-agent repotrectinib treatment significantly inhibited tumor growth, and the combination with Gefitinib and Trametinib further prolonged mouse survival
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