TPX-0131

• CAS: 2648641-36-3
• Catalog Number: ACM2648641363
• Category: Inhibitors
• Molecular Weight: 447.42
• Molecular Formula: C21H20F3N5O3
• 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.
• Synonyms: TPX-0131; TPX 0131; TPX0131
• IUPAC 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
• Canonical SMILES: FC([C@H]1N2C3=NC4=C(C(NC(C)(COC5=CC=C(F)C=C5C2)C)=O)C=NN4C=C3OC1)F
• InChI: 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
• InChI Key: ILAMRXVQSGVCJX-AWEZNQCLSA-N
• Solubility: To be determined
• Appearance: Solid powder
• Shelf Life: >2 years if stored properly
• Storage: Dry, dark and at 0-4 °C for short term (days to weeks) or -20 °C for long term (months to years).
• 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.
• Drug Formulation: To be determined
• Elemental Analysis: C, 56.37; H, 4.51; F, 12.74; N, 15.65; O, 10.73
• Exact Mass: 447.1518
• HS Tariff Code: 2934.99.9001
• 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/
• Shipping: 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.
• Stock Solution Storage: 0-4 °C for short term (days to weeks), or -20 °C for long term (months).