Synonym
TPX-0131; TPX 0131; TPX0131; Zotizalkib;
IUPAC/Chemical Name
(S,14aE,15aE)-13-(difluoromethyl)-35-fluoro-6,6-dimethyl-13,14-dihydro-12H-4-oxa-7-aza-1(4,6)-pyrazolo[1',5':1,2]pyrimido[5,4-b][1,4]oxazina-3(1,2)-benzenacyclooctaphan-8-one
InChi Key
ILAMRXVQSGVCJX-AWEZNQCLSA-N
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
SMILES Code
FC([C@H]1N2C3=NC4=C(C(NC(C)(COC5=CC=C(F)C=C5C2)C)=O)C=NN4C=C3OC1)F
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
To be determined
Shelf Life
>2 years if stored properly
Drug Formulation
To be determined
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
TPX-0131 is a potent, selective, CNS-penetrant inhibitor of wild-type ALK (IC50 of 1.4 nM) and ALK-resistant mutation, e.g. G1202R (IC50 of 0.3 nM), L1196M (IC50 of 0.3 nM) that has strong antitumor activities.
In vitro activity:
TPX-0131 suppressed autophosphorylation of Tyr1604 and Tyr1282/1283 residues of ALK oncogenic fusion proteins in engineered stable cell lines expressing WT or mutant ALK fusion proteins. TPX-0131 exhibited comparable activity to lorlatinib in suppressing WT EML4-ALK phosphorylation with an IC50 value of approximately 3 to 10 nmol/L. TPX-0131 was a potent inhibitor of ALK autophosphorylation in Ba/F3 cells expressing EML4-ALK G1202R solvent front, EML4-ALK G1202R/L1196M, or EML4-ALK G1202R/L1198F mutations, with IC50 values of approximately 3 to 10 nmol/L. In conclusion, TPX-0131 demonstrates potent inhibition of both single and compound EML4-ALK resistance mutations by TPX-0131.
Reference: Mol Cancer Ther. 2021 Sep;20(9):1499-1507. https://pubmed.ncbi.nlm.nih.gov/34158340/
In vivo activity:
The correlation of inhibition of ALK phosphorylation (Tyr1282/1283) was evaluated as a function of TPX-0131 plasma exposure analysis using the Ba/F3 CDX model harboring the EML4-ALK fusion with the G1202R/L1196M compound mutation. For 2 and 5 mg/kg doses of TPX-0131, near complete suppression of phospho-ALK (92%–95%) was observed. However, 12 hours after single-dose TPX-0131 administration, the level phospho-ALK suppression was reduced (0%–63%) consistent with the use of a BID dosing regimen in mouse models. TPX-0131 exhibited more than 90% phosphorylation inhibition of EML4-ALK G1202R/L1196M fusion at a mean free plasma concentration of 19.5 nmol/L. Tumor growth inhibition correlates with TPX-0131 exposure and suppression of ALK phosphorylation. Taken together, TPX-0131 demonstrated marked antitumor effects in Ba/F3 CDX models of ALK resistance mutations such as the G1202R solvent front mutation, the G1202R/L1198F compound mutation, and the gatekeeper/solvent front compound mutation G1202R/L1196M.
Reference: Mol Cancer Ther. 2021 Sep;20(9):1499-1507. https://pubmed.ncbi.nlm.nih.gov/34158340/
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
25.0 |
55.88 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
447.42
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Murray BW, Zhai D, Deng W, Zhang X, Ung J, Nguyen V, Zhang H, Barrera M, Parra A, Cowell J, Lee DJ, Aloysius H, Rogers E. TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations. Mol Cancer Ther. 2021 Sep;20(9):1499-1507. doi: 10.1158/1535-7163.MCT-21-0221. Epub 2021 Jun 22. PMID: 34158340.
In vitro protocol:
1. Murray BW, Zhai D, Deng W, Zhang X, Ung J, Nguyen V, Zhang H, Barrera M, Parra A, Cowell J, Lee DJ, Aloysius H, Rogers E. TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations. Mol Cancer Ther. 2021 Sep;20(9):1499-1507. doi: 10.1158/1535-7163.MCT-21-0221. Epub 2021 Jun 22. PMID: 34158340.
In vivo protocol:
1. Murray BW, Zhai D, Deng W, Zhang X, Ung J, Nguyen V, Zhang H, Barrera M, Parra A, Cowell J, Lee DJ, Aloysius H, Rogers E. TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations. Mol Cancer Ther. 2021 Sep;20(9):1499-1507. doi: 10.1158/1535-7163.MCT-21-0221. Epub 2021 Jun 22. PMID: 34158340.
1: Ou SI, Nagasaka M, Brazel D, Hou Y, Zhu VW. Will the clinical development of 4th-generation "double mutant active" ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC? Transl Oncol. 2021 Nov;14(11):101191. doi: 10.1016/j.tranon.2021.101191. Epub 2021 Aug 5. PMID: 34365220; PMCID: PMC8353359.
2: Murray BW, Zhai D, Deng W, Zhang X, Ung J, Nguyen V, Zhang H, Barrera M, Parra A, Cowell J, Lee DJ, Aloysius H, Rogers E. TPX-0131, a Potent CNS- penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations. Mol Cancer Ther. 2021 Sep;20(9):1499-1507. doi: 10.1158/1535-7163.MCT-21-0221. Epub 2021 Jun 22. PMID: 34158340.
