Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type
PMID
Authors J. Jean Cui, Evan Rogers, Dayong Zhai, Wei Deng, Jane Ung, Vivian Nguyen, Han Zhang, Xin Zhang, Ana Parra, Maria Barrera, Dong Lee, Brion Murray
Title A next generation macrocyclic ALK inhibitor that overcomes ALK resistant mutations refractory to current approved ALK inhibitors
Journal
Vol
Issue
Date
URL https://vcusa.sparx-ip.net/aacr2020ep/?c=a&searchfor=TPX-0131&view=2&item=2020AB_5226
Abstract Text Anaplastic lymphoma kinase (ALK) gene rearrangements occur in up to 7% of patients with non-small cell lung cancer (NSCLC) with the majority as EML4-ALK fusions. Crizotinib (first generation ALK inhibitor) was the first approved ALK inhibitor for the treatment of ALK-positive metastatic non-small cell lung cancer. However, development of resistance to crizotinib caused by secondary kinase domain mutations, bypass signaling, or morphology changes occurs. Second generation ALK inhibitors alectinib, ceritinib, and brigatinib were able to overcome the majority of ALK resistant mutations (L1196M, G1269A and F1174L) acquired with crizotinib. The solvent front mutation (SFM) G1202R is a common resistant mutation to crizotinib and the second generation ALK inhibitors. Lorlatinib, a third generation ALK inhibitor, can overcome G1202R resistance with moderate IC50 values of 40 - 60 nM in cell-based assays. Although, compound mutations such as ones with both gatekeeper and solvent front mutations (L1196M/G1202R) are refractory to lorlatinib, representing an unmet medical need. TPX-0131 is a next generation ALK inhibitor designed with a compact macrocyclic structure that can bind completely within the ATP binding boundary to overcome a variety of ALK resistant mutations, especially SFM G1202R and compound mutations L1196M/G1202R. TPX-0131 potently inhibits wildtype (WT) ALK and over 20 different ALK mutations with IC50 values <5 nM when tested in enzymatic kinase assays in the presence of 10 μM of ATP. In cell proliferation assays, TPX-0131 exhibited comparable antiproliferation activity to the most potent ALK inhibitor lorlatinib in Ba/F3 cells engineered with EML4-ALK WT. Importantly, TPX-0131 is more than 100-fold more potent against G1202R than lorlatinib in cell proliferation assays. Furthermore, TPX-0131 demonstrated antiproliferation IC50 values <2 nM in Ba/F3 cell models engineered with compound mutations including L1196M/G1202R, L1198F/G1202R, L1196M/L1198F, and C1156Y/G1202R, while lorlatinib and other ALK inhibitors are not active (IC50s >1 μM). Taken together, TPX-0131 is a next generation ALK inhibitor that can overcome a broad spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations (e.g. L1196M/G1202R). The nonclinical pharmacology profile of TPX-0131 warrants further preclinical investigation.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
TPX-0131 ALK Inhibitor 23 TPX-0131 is a small molecule that binds completely within the ATP-binding pocket of Alk, which may lead to inhibition of tumor cells harboring ALK mutations (AACR Virtual Annual Meeting II (Jun 2020), Abstract 5226).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK I1171T Advanced Solid Tumor decreased response TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 demonstrated reduced growth inhibition of transformed cells expressing ALK I1171T in the context of EML4-ALK in culture (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK C1156Y ALK L1198F Advanced Solid Tumor predicted - sensitive TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing ALK C1156Y and ALK L1198F compound mutation in the context of EML4-ALK in culture (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK G1269A Advanced Solid Tumor predicted - sensitive TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing ALK G1269A in the context of EML4-ALK in culture (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK Advanced Solid Tumor predicted - sensitive TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing EML4-ALK in culture (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK G1202R ALK G1269A Advanced Solid Tumor predicted - sensitive TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing ALK G1202R and ALK G1269A compound mutation in the context of EML4-ALK in culture (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK G1269S Advanced Solid Tumor decreased response TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 demonstrated reduced growth inhibition of transformed cells expressing ALK G1269S in the context of EML4-ALK in culture (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK L1198F ALK G1202R Advanced Solid Tumor predicted - sensitive TPX-0131 Preclinical - Cell line xenograft Actionable In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing ALK L1198F and ALK G1202R compound mutation in the context of EML4-ALK in culture, and inhibited tumor growth in a cell line xenograft model (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK L1198F ALK G1202R ALK G1269A Advanced Solid Tumor predicted - sensitive TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing ALK L1198F, ALK G1202R, and ALK G1269A compound mutation in the context of EML4-ALK in culture (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK I1171S Advanced Solid Tumor decreased response TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 demonstrated reduced growth inhibition of transformed cells expressing ALK I1171S in the context of EML4-ALK in culture (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK L1196M ALK G1202R Advanced Solid Tumor predicted - sensitive TPX-0131 Preclinical - Cell line xenograft Actionable In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing ALK L1196M and ALK G1202R compound mutation in the context of EML4-ALK in culture, and inhibited tumor growth in a cell line xenograft model (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK L1196M ALK L1198F Advanced Solid Tumor predicted - sensitive TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing ALK L1196M and ALK L1198F compound mutation in the context of EML4-ALK in culture (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK I1171N Advanced Solid Tumor decreased response TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 demonstrated reduced growth inhibition of transformed cells expressing ALK I1171N in the context of EML4-ALK in culture (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK G1202R ALK L1204V ALK G1269A Advanced Solid Tumor predicted - sensitive TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing ALK G1202R, ALK L1204V, and ALK G1269A compound mutation in the context of EML4-ALK in culture (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK G1202R Advanced Solid Tumor predicted - sensitive TPX-0131 Preclinical - Cell line xenograft Actionable In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing ALK G1202R in the context of EML4-ALK in culture, and inhibited tumor growth in a cell line xenograft model (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK L1198F Advanced Solid Tumor predicted - sensitive TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing ALK L1198F in the context of EML4-ALK in culture (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...
EML4 - ALK ALK C1156Y ALK G1202R Advanced Solid Tumor predicted - sensitive TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing ALK C1156Y and ALK G1202R compound mutation in the context of EML4-ALK in culture (AACR Virtual Annual Meeting II (Jun 2020), Abstract 52226). detail...