WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 556040
CAS#: 2648641-36-3
Description: TPX-0131 is a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations. In cellular assays, TPX-0131 was more potent than all five approved ALK inhibitors against WT ALK and many types of ALK resistance mutations, e.g., G1202R, L1196M, and compound mutations. In biochemical assays, TPX-0131 potently inhibited (IC50 <10 nmol/L) WT ALK and 26 ALK mutants (single and compound mutations). TPX-0131, but not lorlatinib, caused complete tumor regression in ALK (G1202R) and ALK compound mutation-dependent xenograft models. Following repeat oral administration of TPX-0131 to rats, brain levels of TPX-0131 were approximately 66% of those observed in plasma.
MedKoo Cat#: 556040
Name: TPX-0131
CAS#: 2648641-36-3
Chemical Formula: C21H20F3N5O3
Exact Mass: 447.1518
Molecular Weight: 447.4182
Elemental Analysis: C, 56.37; H, 4.51; F, 12.74; N, 15.65; O, 10.73
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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
Appearance: Solid powder
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 | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 25.0 | 55.88 |
The following data is based on the product molecular weight 447.4182 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.
