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Purity: =100%
Repotrectinib (TPX-0005, TPX0005; Augtyro) is a novel, oral, rationally-designed, highly potent inhibitor of ALK/ROS1/TRK with IC50 of 5.3 nM, 1.01 nM, 1.26 nM and 1.08 nM for SRC, WT ALK, ALK G1202R and ALK L1196M, respectively. It has potential anticancer activity. It successfully overcomes this primary resistance (IC50 100 nM in the cell proliferation assay) by strongly inhibiting the SRC substrate paxillin (IC50 107 nM) and EML4-ALK phosphorylation (IC50 13 nM). Similar to saracatinib, PX-0005 also inhibits H2228 cell migration in a wound healing assay. With its ability to overcome various ALK resistance mechanisms, such as secondary mutations, bypass signaling activation, and EMT, TPX-0005 has an overall very favorable profile and merits further clinical investigation. Repotrectinib (Augtyro) was approved in 2023 by FDA for treating ROS1-positive NSCLC.
| Targets |
WT ALK (IC50 = 1.01 nM); ALK(L1196M) (IC50 = 1.08 nM); ALK(G1202R) (IC50 = 1.26 nM); Trk receptor; ROS1
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| ln Vitro |
TPX-0005 is an orally available and potent ATP-competitive inhibitor that can be taken orally and is effective against clinically resistant mutants of ALK, ROS1, TRKA, TRKB, and TRKC recombinant kinases. Through the inhibition of target phosphorylation and concurrent inactivation of downstream effectors like ERK, AKT, and STAT3, TPX-0005 exhibits strong anti-proliferative activity in the range of sub-nanomolar to low nanomolar in a number of human cancer cell lines and engineered stable cell lines expressing the targeted oncogenes or their solvent front mutants[2]. Similar to saracatinib, TPX-0005 also inhibits H2228 cell migration in a wound healing assay. In addition to inhibiting a wide range of mutant ALKs and the wild-type ALK, TPX-0005 can suppress metastatic features by inhibiting SRC, which also helps it overcome primary resistance[1].
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| ln Vivo |
TPX-0005 treatment results in significant regression of tumors harboring the oncogenic ALK, ROS1 and TRKC fusions in patient derived xenograft tumor models. Additionally, via inhibition of target phosphorylation, TPX-0005 demonstrates strong anti-tumor activity in a number of mouse xenograft tumor models in tumors containing solvent front mutation-carrying oncogenes as well as tumors containing wildtype oncogenic targets[2].
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| Enzyme Assay |
TPX-0005 is a novel, rationally-designed, highly potent ALK/ROS1/TRK inhibitor, has IC50 values of 5.3 nM, 1.01 nM, 1.26 nM, and 1.08 nM for SRC, WT ALK, ALK G1202R, and ALK L1196M, in that order. It might possess anticancer properties. By significantly inhibiting the phosphorylation of EML4-ALK (IC50 13 nM) and the SRC substrate paxillin (IC50 107 nM), it successfully overcomes this primary resistance (IC50 100 nM in the cell proliferation assay). In a wound healing assay, PX-0005 inhibits H2228 cell migration with activity comparable to that of saracatinib. All things considered, TPX-0005 has a very promising profile and is capable of defeating several ALK resistance mechanisms, such as secondary mutations, bypass signaling activation, and EMT. As such, it deserves further clinical research.
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| Cell Assay |
TPX-0005 is also a potent SRC inhibitor (IC50 5.3 nM). In tests of cell proliferation, the increased SRC kinase activity in the H2228 lung cancer cell line confers resistance to crizotinib (IC50 1200 nM) and ceritinib (IC50 1000 nM). With strong inhibition of the phosphorylation of EML4-ALK (IC50 13 nM) and the SRC substrate paxillin (IC50 107 nM), as well as other downstream signaling targets, TPX-0005 effectively overcame this primary resistance (IC50 100 nM in cell proliferation assay). Similar to saracatinib, TPX-0005 inhibited H2228 cell migration in a wound healing assay.
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| References |
| Molecular Formula |
C18H18FN5O2
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|---|---|
| Molecular Weight |
355.37
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| Exact Mass |
355.14
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| Elemental Analysis |
C, 60.84; H, 5.11; F, 5.35; N, 19.71; O, 9.00
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| CAS # |
1802220-02-5
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| Related CAS # |
1802220-02-5; 2058227-19-1
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| Appearance |
Solid powder
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| SMILES |
C[C@H]1CNC(=O)C2=C3N=C(C=CN3N=C2)N[C@@H](C4=C(O1)C=CC(=C4)F)C
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| InChi Key |
FIKPXCOQUIZNHB-WDEREUQCSA-N
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| InChi Code |
InChI=1S/C18H18FN5O2/c1-10-8-20-18(25)14-9-21-24-6-5-16(23-17(14)24)22-11(2)13-7-12(19)3-4-15(13)26-10/h3-7,9-11H,8H2,1-2H3,(H,20,25)(H,22,23)/t10-,11+/m0/s1
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| Chemical Name |
(3R,11S)-6-fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one
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| Synonyms |
Ropotrectinib; TPX0005; TPX-0005; TPX 0005; Augtyro
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.03 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.03 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8140 mL | 14.0698 mL | 28.1397 mL | |
| 5 mM | 0.5628 mL | 2.8140 mL | 5.6279 mL | |
| 10 mM | 0.2814 mL | 1.4070 mL | 2.8140 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04094610 | Recruiting | Drug: Oral repotrectinib (TPX-0005) |
Lymphoma Primary CNS Tumors |
Turning Point Therapeutics, Inc. | March 12, 2020 | Phase 1 Phase 2 |
| NCT05004116 | Recruiting | Drug: Irinotecan and temozolomide Drug: Repotrectinib |
Advanced Cancer Metastatic Solid Tumor |
Memorial Sloan Kettering Cancer Center |
August 9, 2021 | Phase 1 Phase 2 |
| NCT04772235 | Recruiting | Drug: Repotrectinib Drug: Osimertinib |
Nsclc | Instituto Oncológico Dr Rosell | February 11, 2022 | Phase 1 |
| NCT05828303 | Recruiting | Drug: TPX-0005 Drug: Digoxin |
Advanced Solid Tumor Metastatic Solid Tumor |
Turning Point Therapeutics, Inc. | July 28, 2022 | Phase 1 |
| NCT03093116 | Recruiting | Drug: Oral repotrectinib (TPX-0005) |
Locally Advanced Solid Tumors Metastatic Solid Tumors |
Turning Point Therapeutics, Inc. | February 27, 2017 | Phase 1 Phase 2 |
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