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Ref Type

Journal Article

PMID

(34158340)

Authors

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

Title

TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	20	9	2021 09	1499-1507	Mol Cancer Ther

URL

Abstract Text

Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung cancer. Each generation of ALK inhibitor showed improvements in terms of central nervous system (CNS) penetration and potency against wild-type (WT) ALK, yet a key continued limitation is their susceptibility to resistance from ALK active-site mutations. The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations in cis, compound mutations). TPX-0131 is a compact macrocyclic molecule designed to fit within the ATP-binding boundary to inhibit ALK fusion proteins. 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. Taken together, preclinical studies show that TPX-0131 is a CNS-penetrant, next-generation ALK inhibitor that has potency against WT ALK and a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, for which there are currently no effective therapies.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
TPX-0131	TPX-0131	56	1

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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
TPX-0131		TPX 0131\|TPX0131\|Zotizalkib	ALK Inhibitor 33	TPX-0131 is a small molecule that binds completely within the ATP-binding pocket of Alk, which may lead to inhibition of ALK signaling, proliferation, and tumor growth (PMID: 34158340).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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Showing 1 to 87 of 87 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK G1202R	Advanced Solid Tumor	conflicting	Lorlatinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Lorbrena (lorlatinib) treatment inhibited tumor growth in a mouse cell line xenograft model expressing EML4-ALK and ALK G1202R (PMID: 34158340).	34158340
EML4 - ALK ALK G1202R	Advanced Solid Tumor	sensitive	TPX-0131	Preclinical - Cell line xenograft	Actionable	In a preclinical study, TPX-0131 inhibited Alk autophosphorylation and proliferation of transformed cells expressing ALK G1202R in the context of EML4-ALK in culture and resulted in complete tumor growth inhibition in a mouse cell line xenograft model (PMID: 34158340).	34158340
EML4 - ALK ALK L1196M ALK G1202R	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Lorbrena (lorlatinib) treatment did not inhibit proliferation of transformed cells expressing ALK G1202R and L1196M compound mutation in the context of EML4-ALK in culture and resulted in only 18% tumor growth inhibition in a mouse cell line xenograft model (PMID: 34158340).	34158340
EML4 - ALK ALK L1196M ALK G1202R	Advanced Solid Tumor	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 resulted in complete tumor growth regression in a cell line xenograft model (PMID: 34158340).	34158340
EML4 - ALK ALK L1198F ALK G1202R	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Lorbrena (lorlatinib) treatment did not inhibit proliferation of transformed cells expressing ALK G1202R and L1198F compound mutation in the context of EML4-ALK culture and resulted in only 30% tumor growth inhibition in a mouse cell line xenograft model (PMID: 34158340).	34158340
EML4 - ALK ALK L1198F ALK G1202R	Advanced Solid Tumor	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 resulted in complete tumor growth regression in a cell line xenograft model (PMID: 34158340).	34158340
EML4 - ALK ALK G1202R ALK L1204V ALK G1269A	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R, L1204V, and G1269A compound mutation in the context of EML4-ALK were resistant to Lorbrena (lorlatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK	Advanced Solid Tumor	sensitive	TPX-0131	Preclinical - Cell culture	Actionable	In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing EML4-ALK in culture (PMID: 34158340).	34158340
EML4 - ALK ALK C1156Y ALK G1202R	Advanced Solid Tumor	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R and C1156Y compound mutation in the context of EML4-ALK were resistant to Zykadia (ceritinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK C1156Y ALK G1202R	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R and ALK C1156Y compound mutation in the context of EML4-ALK were resistant to Xalkori (crizotinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK C1156Y ALK G1202R	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R and C1156Y compound mutation in the context of EML4-ALK were resistant to Lorbrena (lorlatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK C1156Y ALK G1202R	Advanced Solid Tumor	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 (PMID: 34158340).	34158340
EML4 - ALK ALK C1156Y ALK G1202R	Advanced Solid Tumor	resistant	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK C1156Y and G1202R compound mutation in the context of EML4-ALK were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK C1156Y ALK G1202R	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R and ALK C1156Y compound mutation in the context of EML4-ALK were resistant to Alecensa (alectinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK C1156Y ALK L1198F	Advanced Solid Tumor	conflicting	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK C1156Y and L1198F compound mutation in the context of EML4-ALK were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK C1156Y ALK L1198F	Advanced Solid Tumor	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK C1156Y and L1198F compound mutation in the context of EML4-ALK were resistant to Zykadia (ceritinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK C1156Y ALK L1198F	Advanced Solid Tumor	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 (PMID: 34158340).	34158340
EML4 - ALK ALK C1156Y ALK L1198F	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK C1156Y and L1198F compound mutation in the context of EML4-ALK were resistant to Lorbrena (lorlatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK C1156Y ALK L1198F	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK C1156Y and ALK L1198F compound mutation in the context of EML4-ALK were resistant to Alecensa (alectinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK G1202R ALK G1269A	Advanced Solid Tumor	resistant	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1269A and G1202R compound mutation in the context of EML4-ALK were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK G1202R ALK G1269A	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R and G1269A compound mutation in the context of EML4-ALK were resistant to Lorbrena (lorlatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK G1202R ALK G1269A	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R and ALK G1269A compound mutation in the context of EML4-ALK were resistant to Xalkori (crizotinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK G1202R ALK G1269A	Advanced Solid Tumor	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R and G1269A compound mutation in the context of EML4-ALK were resistant to Zykadia (ceritinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK G1202R ALK G1269A	Advanced Solid Tumor	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 (PMID: 34158340).	34158340
EML4 - ALK ALK G1202R ALK G1269A	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R and ALK G1269A compound mutation in the context of EML4-ALK were resistant to Alecensa (alectinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK G1202R ALK L1204V ALK G1269A	Advanced Solid Tumor	resistant	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1269A, L1204V, and G1202R compound mutation in the context of EML4-ALK were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK G1202R ALK L1204V ALK G1269A	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R, G1269A, and L1204V compound mutation in the context of EML4-ALK were resistant to Alecensa (alectinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK G1202R ALK L1204V ALK G1269A	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R, L1204V, and G1269A compound mutation in the context of EML4-ALK were resistant to Xalkori (crizotinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK G1202R ALK L1204V ALK G1269A	Advanced Solid Tumor	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 (PMID: 34158340).	34158340
EML4 - ALK ALK G1202R ALK L1204V ALK G1269A	Advanced Solid Tumor	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R, L1204V, and G1269A compound mutation in the context of EML4-ALK were resistant to Zykadia (ceritinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK G1269A	Advanced Solid Tumor	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 (PMID: 34158340).	34158340
EML4 - ALK ALK G1269S	Advanced Solid Tumor	resistant	TPX-0131	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1269S in the context of EML4-ALK were resistant to TPX-0131 in culture (PMID: 34158340).	34158340
EML4 - ALK ALK I1171N	Advanced Solid Tumor	resistant	TPX-0131	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK I1171N in the context of EML4-ALK were resistant to TPX-0131 in culture (PMID: 34158340).	34158340
EML4 - ALK ALK I1171N ALK L1198F	Advanced Solid Tumor	sensitive	TPX-0131	Preclinical - Cell culture	Actionable	In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing ALK I1171N and ALK L1198F compound mutation in the context of EML4-ALK in culture (PMID: 34158340).	34158340
EML4 - ALK ALK I1171N ALK L1198F	Advanced Solid Tumor	resistant	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK I1171N and L1198F compound mutation in the context of EML4-ALK were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK I1171N ALK L1198F	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK I1171N and L1198F compound mutation in the context of EML4-ALK were resistant to Lorbrena (lorlatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK I1171N ALK L1198F	Advanced Solid Tumor	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK I1171N and L1198F compound mutation in the context of EML4-ALK were resistant to Zykadia (ceritinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK I1171N ALK L1198F	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK I1171N and ALK L1198F compound mutation in the context of EML4-ALK were resistant to Alecensa (alectinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK I1171N ALK L1198F	Advanced Solid Tumor	conflicting	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK I1171N and ALK L1198F compound mutation in the context of EML4-ALK were resistant to Xalkori (crizotinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK I1171S	Advanced Solid Tumor	resistant	TPX-0131	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK I1171S in the context of EML4-ALK were resistant to TPX-0131 in culture (PMID: 34158340).	34158340
EML4 - ALK ALK I1171T	Advanced Solid Tumor	resistant	TPX-0131	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK I1171T in the context of EML4-ALK were resistant to TPX-0131 in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1196M	Advanced Solid Tumor	sensitive	TPX-0131	Preclinical - Cell culture	Actionable	In a preclinical study, TPX-0131 inhibited proliferation of transformed cells expressing ALK L1196M in the context of EML4-ALK in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1196M ALK G1202R	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R and ALK L1196M compound mutation in the context of EML4-ALK were resistant to Alecensa (alectinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1196M ALK G1202R	Advanced Solid Tumor	resistant	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK L1196M and G1202R compound mutation in the context of EML4-ALK were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1196M ALK G1202R	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R and ALK L1196M compound mutation in the context of EML4-ALK were resistant to Xalkori (crizotinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1196M ALK G1202R	Advanced Solid Tumor	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R and L1196M compound mutation in the context of EML4-ALK were resistant to Zykadia (ceritinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1196M ALK L1198F	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK L1196M and ALK L1198F compound mutation in the context of EML4-ALK were resistant to Xalkori (crizotinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1196M ALK L1198F	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK L1196M and ALK L1198F compound mutation in the context of EML4-ALK were resistant to Alecensa (alectinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1196M ALK L1198F	Advanced Solid Tumor	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 (PMID: 34158340).	34158340
EML4 - ALK ALK L1196M ALK L1198F	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK L1196M and L1198F compound mutation in the context of EML4-ALK were resistant to Lorbrena (lorlatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1196M ALK L1198F	Advanced Solid Tumor	resistant	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK L1196M and L1198F compound mutation in the context of EML4-ALK were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1196M ALK L1198F	Advanced Solid Tumor	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK L1196M and L1198F compound mutation in the context of EML4-ALK were resistant to Zykadia (ceritinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1198F	Advanced Solid Tumor	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 (PMID: 34158340).	34158340
EML4 - ALK ALK L1198F ALK G1202R	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R and ALK L1198F compound mutation in the context of EML4-ALK were resistant to Alecensa (alectinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1198F ALK G1202R	Advanced Solid Tumor	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R and L1198F compound mutation in the context of EML4-ALK were resistant to Zykadia (ceritinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1198F ALK G1202R	Advanced Solid Tumor	resistant	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK L1198F and G1202R compound mutation in the context of EML4-ALK were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1198F ALK G1202R ALK G1269A	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R, L1198F, and G1269A compound mutation in the context of EML4-ALK were resistant to Xalkori (crizotinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1198F ALK G1202R ALK G1269A	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R, G1269A, and L1198F compound mutation in the context of EML4-ALK were resistant to Alecensa (alectinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1198F ALK G1202R ALK G1269A	Advanced Solid Tumor	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R, L1198F, and G1269A compound mutation in the context of EML4-ALK were resistant to Zykadia (ceritinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1198F ALK G1202R ALK G1269A	Advanced Solid Tumor	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 (PMID: 34158340).	34158340
EML4 - ALK ALK L1198F ALK G1202R ALK G1269A	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1202R, L1198F, and G1269A compound mutation in the context of EML4-ALK were resistant to Lorbrena (lorlatinib) treatment in culture (PMID: 34158340).	34158340
EML4 - ALK ALK L1198F ALK G1202R ALK G1269A	Advanced Solid Tumor	resistant	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK G1269A, L1198F, and G1202R compound mutation in the context of EML4-ALK were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 34158340).	34158340
ALK C1156Y	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK C1156Y in an in vitro assay (PMID: 34158340).	34158340
ALK C1156Y ALK L1198F	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK C1156Y and ALK L1198F compound mutation in an in vitro assay (PMID: 34158340).	34158340
ALK D1203N	Advanced Solid Tumor	decreased response	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, ALK D1203N demonstrated reduced sensitivity to TPX-0131 in an in vitro kinase assay (PMID: 34158340).	34158340
ALK D1203N ALK E1210K	Advanced Solid Tumor	decreased response	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, ALK D1203N and E1210K compound mutation demonstrated reduced sensitivity to TPX-0131 in an in vitro kinase assay (PMID: 34158340).	34158340
ALK E1210K	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK E1210K in an in vitro assay (PMID: 34158340).	34158340
ALK F1174C	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK F1174C in an in vitro assay (PMID: 34158340).	34158340
ALK F1174L	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK F1174L in an in vitro assay (PMID: 34158340).	34158340
ALK F1174S	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK F1174S in an in vitro assay (PMID: 34158340).	34158340
ALK F1245C	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK F1245C in an in vitro assay (PMID: 34158340).	34158340
ALK G1202del	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK G1202del in an in vitro assay (PMID: 34158340).	34158340
ALK G1269A	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK G1269A in an in vitro assay (PMID: 34158340).	34158340
ALK G1269S	Advanced Solid Tumor	decreased response	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, ALK G1269S demonstrated reduced sensitivity to TPX-0131 in an in vitro kinase assay (PMID: 34158340).	34158340
ALK I1171N	Advanced Solid Tumor	decreased response	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, ALK I1171N demonstrated reduced sensitivity to TPX-0131 in an in vitro kinase assay (PMID: 34158340).	34158340
ALK L1152P	Advanced Solid Tumor	decreased response	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, ALK L1152P demonstrated reduced sensitivity to TPX-0131 in an in vitro kinase assay (PMID: 34158340).	34158340
ALK L1152R	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK L1152R in an in vitro assay (PMID: 34158340).	34158340
ALK L1196M	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK L1196M in an in vitro assay (PMID: 34158340).	34158340
ALK L1196M ALK L1198F	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK L1196M and ALK L1198F compound mutation in an in vitro assay (PMID: 34158340).	34158340
ALK L1198F	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK L1198F in an in vitro assay (PMID: 34158340).	34158340
ALK L1198F ALK G1202R	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK G1202R and L1198F compound mutation in an in vitro assay (PMID: 34158340).	34158340
ALK R1275Q	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK R1275Q in an in vitro assay (PMID: 34158340).	34158340
ALK S1206C ALK E1210K	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK S1206C and ALK E1210K compound mutation in an in vitro assay (PMID: 34158340).	34158340
ALK S1206R	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK S1206R in an in vitro assay (PMID: 34158340).	34158340
ALK T1151dup	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK T1151dup in an in vitro assay (PMID: 34158340).	34158340
ALK T1151M	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK T1151M in an in vitro assay (PMID: 34158340).	34158340
ALK V1180L	Advanced Solid Tumor	predicted - sensitive	TPX-0131	Preclinical - Biochemical	Actionable	In a preclinical study, TPX-0131 inhibited kinase activity of ALK V1180L in an in vitro assay (PMID: 34158340).	34158340

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