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Zotizalkib (TPX 0131; TPX-0131) is a novel, potent CNS-penetrant ALK inhibitor with anticancer activity. TPX-0131 demonstrated greater potency against WT ALK and various ALK resistance mutations in cellular assays compared to all five approved ALK inhibitors.
| Targets |
Wild-typr AKT (IC50 = 1.4 nM); mutant ALK variants (IC50 = 0.2-6.6 nM)
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|---|---|
| ln Vitro |
At an IC50 of 1.4 nM, zoletilkib effectively suppresses 26 ALK variants as well as wild-type ALK. The ALK mutations C1156Y, E1210K/S1206C, L1198F/C1156Y, L1196M/L1198F, E1210K, L1196M, T1151M, canceled G1202, S 1206R, G1202R/ L1198F, F1174L, F1245C, R12 75Q, and G1202R have IC50 values less than 1 nM when zolitizalkib is used. L1198F, L1152R, F1174S, T1151-L1152 insT, V1180L, G126 9A, and F1174C are the ALK mutations for which ozotizalkib has IC50 values of 1-2 nM. IC50 values of 2-7 nM indicate that zoletizalkib exhibits limited action against ALK mutations, including I1171N, L1152P, D1203N, D1203N/E1210K, and G1269S [1]. When applied to Ba/F3 cells carrying EML4-ALK G1202R, EML4-ALK G1202R/L1196M, or EML4-ALK G1202R/L1198F mutations, zoltizalkib effectively replaces ALK autophosphorylation; its IC50 value is roughly 3-10 nM [1].
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| ln Vivo |
Tumor growth inhibition (TGI) of 64%, 120%, and 200% at 2 mg/kg, 5 mg/kg, and 10 mg/kg, respectively, was dose-dependently achieved with zolofilkib (2–10 mg/kg; lateral; twice daily; for 2 weeks).
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| Animal Protocol |
Animal/Disease Models: Female SCID/beige mice (5-8 weeks old) with Ba/F3 cells [1]
Doses: 2 mg/kg, 5 mg/kg and 10 mg/kg Route of Administration: (Regression)[ 1]. Bao; twice (two times) daily; for 2 weeks Experimental Results: Causes complete tumor regression in an ALK mutation-dependent xenograft model. |
| References | |
| Additional Infomation |
Zotizalkib is an orally available, compact macrocyclic structure-based inhibitor of the receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK), with potential antineoplastic activity. Upon oral administration, zotizalkib binds within the ATP binding boundary and inhibits ALK wild-type tyrosine kinase, ALK fusion proteins and numerous ALK point mutations, including acquired resistance mutations, such as the solvent front mutation (SFM) G1202R and compound mutations L1196M/G1202R, L1198F/G1202R, L1196M/L1198F, and C1156Y/G1202R. Inhibition of ALK leads to the disruption of ALK-mediated signaling and the inhibition of cell growth in ALK-expressing tumor cells. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development. ALK is not expressed in healthy adult human tissue but ALK dysregulation and gene rearrangements are associated with a variety of tumor cell types. Compared to other ALK inhibitors, zotizalkib is able to inhibit ALK resistance mutations associated with acquired resistance to other ALK inhibitors.
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| Molecular Formula |
C21H20F3N5O3
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|---|---|
| Molecular Weight |
447.4104
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| Exact Mass |
447.15
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| Elemental Analysis |
C, 56.37; H, 4.51; F, 12.74; N, 15.65; O, 10.73
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| CAS # |
2648641-36-3
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| Related CAS # |
2648641-36-3
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| PubChem CID |
156024486
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| Appearance |
White to off-white solid powder
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| LogP |
2.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
32
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| Complexity |
716
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1(COC2=C(CN3[C@@H](COC4=CN5C(=C(C=N5)C(=O)N1)N=C43)C(F)F)C=C(C=C2)F)C
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| InChi Key |
ILAMRXVQSGVCJX-AWEZNQCLSA-N
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| InChi Code |
InChI=1S/C21H20F3N5O3/c1-21(2)10-32-15-4-3-12(22)5-11(15)7-28-14(17(23)24)9-31-16-8-29-18(26-19(16)28)13(6-25-29)20(30)27-21/h3-6,8,14,17H,7,9-10H2,1-2H3,(H,27,30)/t14-/m0/s1
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| Chemical Name |
(18S)-18-(difluoromethyl)-13-fluoro-7,7-dimethyl-9,20-dioxa-1,2,6,17,23-pentazapentacyclo[19.3.1.04,24.010,15.017,22]pentacosa-2,4(24),10(15),11,13,21(25),22-heptaen-5-one
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| Synonyms |
TPX 0131; Zotizalkib; TPX-0131; TPX0131
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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) |
DMSO: ~62.5 mg/mL (~139.7 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.65 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 20.8 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: 2.08 mg/mL (4.65 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.65 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2351 mL | 11.1754 mL | 22.3509 mL | |
| 5 mM | 0.4470 mL | 2.2351 mL | 4.4702 mL | |
| 10 mM | 0.2235 mL | 1.1175 mL | 2.2351 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 |
| NCT04849273 | Terminated | Drug: TPX-0131 | NSCLC Advanced Solid Tumor |
Turning Point Therapeutics, Inc. | July 28, 2021 | Phase 1 |
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