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Ref Type Journal Article
PMID (35421578)
Authors Liu X, Zhang L, Wan H, Zhu Z, Jin J, Qin Y, Mao W, Yan K, Fang D, Jiang W, Hu L, Chen J, Chen K, Chen S, Li J, Zhao S, Zheng S, Zhang L, Ding CZ
Title Discovery and preclinical evaluations of WX-0593, a novel ALK inhibitor targeting crizotinib-resistant mutations.
Journal Bioorganic & medicinal chemistry letters
Vol 66
Issue
Date 2022 Apr 11
URL
Abstract Text ALK gene rearrangements are oncogenic drivers in approximately 5% of NSCLC. Crizotinib, a first generation ALK inhibitor, is widely prescribed for ALK-positive NSCLC in clinic. Resistance to crizotinib and other ALK inhibitors has been problematic. Addressing resistance, here we describe discovery and development of a novel, proprietary spirocyclic diamine-substituted aryl phosphine oxide series of inhibitors, which led to the identification of WX-0593 (16a) as a potent ALK inhibitor. WX-0593 inhibited the activity of both wild type and resistant mutants of ALK in vitro, showed strong antitumor activity in a crizotinib-resistant mouse PDX model. WX-0593 is currently under development in phase II/III clinical trials.

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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
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 I1171S Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 treatment inhibited viability of transformed cells expressing EML4-ALK with ALK I1171S in culture (PMID: 35421578). 35421578
EML4 - ALK ALK F1174C Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK F1174C in culture (PMID: 35421578). 35421578
EML4 - ALK ALK C1156Y Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 inhibited growth of transformed cells expressing ALK C1156Y in the context of EML4-ALK in culture (PMID: 35421578). 35421578
EML4 - ALK ALK T1151dup Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK T1151dup in culture (PMID: 35421578). 35421578
EML4 - ALK ALK F1174L Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 treatment inhibited viability of transformed cells expressing EML4-ALK with ALK F1174L in culture (PMID: 35421578). 35421578
EML4 - ALK ALK G1202R Advanced Solid Tumor conflicting Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK G1202R in culture (PMID: 35421578). 35421578
EML4 - ALK Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 inhibited growth of transformed cells expressing EML4-ALK in culture (PMID: 35421578). 35421578
EML4 - ALK ALK V1180L Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK V1180L in culture (PMID: 35421578). 35421578
EML4 - ALK ALK F1174V Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 treatment inhibited viability of transformed cells expressing EML4-ALK with ALK F1174V in culture (PMID: 35421578). 35421578
EML4 - ALK Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK in culture (PMID: 35421578). 35421578
EML4 - ALK ALK L1152R Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK L1152R in culture (PMID: 35421578). 35421578
EML4 - ALK ALK F1174C Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 treatment inhibited viability of transformed cells expressing EML4-ALK with ALK F1174C in culture (PMID: 35421578). 35421578
EML4 - ALK ALK I1171N Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK I1171N in culture (PMID: 35421578). 35421578
EML4 - ALK ALK T1151dup Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 treatment inhibited viability of transformed cells expressing EML4-ALK with ALK T1151dup in culture (PMID: 35421578). 35421578
EML4 - ALK ALK L1152R Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 treatment inhibited viability of transformed cells expressing EML4-ALK with ALK L1152R in culture (PMID: 35421578). 35421578
EML4 - ALK ALK G1269A Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 treatment inhibited viability of transformed cells expressing EML4-ALK with ALK G1269A in culture (PMID: 35421578). 35421578
EML4 - ALK ALK I1171T Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 treatment inhibited viability of transformed cells expressing EML4-ALK with ALK I1171T in culture (PMID: 35421578). 35421578
EML4 - ALK ALK I1171S Advanced Solid Tumor conflicting Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK I1171S in culture (PMID: 35421578). 35421578
EML4 - ALK ALK L1196M Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 inhibited growth of transformed cells expressing ALK L1196M in the context of EML4-ALK in culture (PMID: 35421578). 35421578
EML4 - ALK ALK V1180L Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 treatment inhibited viability of transformed cells expressing EML4-ALK with ALK V1180L in culture (PMID: 35421578). 35421578
EML4 - ALK ALK G1202R Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 treatment inhibited viability of transformed cells expressing EML4-ALK with ALK G1202R in culture (PMID: 35421578). 35421578
EML4 - ALK ALK L1152P Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK L1152P in culture (PMID: 35421578). 35421578
EML4 - ALK ALK F1174L Advanced Solid Tumor conflicting Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK F1174L in culture (PMID: 35421578). 35421578
EML4 - ALK ALK G1269A Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK G1269A in culture (PMID: 35421578). 35421578
EML4 - ALK ALK I1171T Advanced Solid Tumor predicted - sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK I1171T in culture (PMID: 35421578). 35421578
EML4 - ALK ALK F1174V Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK F1174V in culture (PMID: 35421578). 35421578
EML4 - ALK ALK I1171N Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 treatment inhibited viability of transformed cells expressing EML4-ALK with ALK I1171N in culture (PMID: 35421578). 35421578
EML4 - ALK ALK L1152P Advanced Solid Tumor sensitive WX-0593 Preclinical - Cell culture Actionable In a preclinical study, WX-0593 treatment inhibited viability of transformed cells expressing EML4-ALK with ALK L1152P in culture (PMID: 35421578). 35421578
EML4 - ALK lung non-small cell carcinoma sensitive WX-0593 Preclinical - Pdx Actionable In a preclinical study, WX-0593 inhibited tumor growth in a patient-derived xenograft (PDX) model of non-small cell lung cancer harboring EML4-ALK (PMID: 35421578). 35421578