Reference Detail

Ref Type Journal Article
PMID (22203728)
Authors Cheng M, Quail MR, Gingrich DE, Ott GR, Lu L, Wan W, Albom MS, Angeles TS, Aimone LD, Cristofani F, Machiorlatti R, Abele C, Ator MA, Dorsey BD, Inghirami G, Ruggeri BA
Title CEP-28122, a highly potent and selective orally active inhibitor of anaplastic lymphoma kinase with antitumor activity in experimental models of human cancers.
Journal Molecular cancer therapeutics
Vol 11
Issue 3
Date 2012 Mar
URL
Abstract Text Anaplastic lymphoma kinase (ALK) is constitutively activated in a number of human cancer types due to chromosomal translocations, point mutations, and gene amplification and has emerged as an excellent molecular target for cancer therapy. Here we report the identification and preclinical characterization of CEP-28122, a highly potent and selective orally active ALK inhibitor. CEP-28122 is a potent inhibitor of recombinant ALK activity and cellular ALK tyrosine phosphorylation. It induced concentration-dependent growth inhibition/cytotoxicity of ALK-positive anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastoma cells, and displayed dose-dependent inhibition of ALK tyrosine phosphorylation in tumor xenografts in mice, with substantial target inhibition (>90%) for more than 12 hours following single oral dosing at 30 mg/kg. Dose-dependent antitumor activity was observed in ALK-positive ALCL, NSCLC, and neuroblastoma tumor xenografts in mice administered CEP-28122 orally, with complete/near complete tumor regressions observed following treatment at doses of 30 mg/kg twice daily or higher. Treatment of mice bearing Sup-M2 tumor xenografts for 4 weeks and primary human ALCL tumor grafts for 2 weeks at 55 or 100 mg/kg twice daily led to sustained tumor regression in all mice, with no tumor reemergence for more than 60 days postcessation of treatment. Conversely, CEP-28122 displayed marginal antitumor activity against ALK-negative human tumor xenografts under the same dosing regimens. Administration of CEP-28122 was well tolerated in mice and rats. In summary, CEP-28122 is a highly potent and selective orally active ALK inhibitor with a favorable pharmaceutical and pharmacokinetic profile and robust and selective pharmacologic efficacy against ALK-positive human cancer cells and tumor xenograft models in mice.

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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
CEP-28122 CEP-28122 10 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CEP-28122 ALK Inhibitor 20 CEP-28122 is a small molecule inhibitor of ALK that inhibits growth of ALK-positive tumors (PMID: 22203728).
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 lung non-small cell carcinoma sensitive CEP-28122 Preclinical - Cell line xenograft Actionable In a preclinical study, CEP-28122 inhibited growth of non-small cell lung carcinoma cell lines harboring EML4-ALK in culture, and resulted in tumor regression in cell line xenograft models (PMID: 22203728). 22203728
ALK negative leukemia resistant CEP-28122 Preclinical - Cell culture Actionable In a preclinical study, CEP-28122 did not inhibit growth of ALK-negative leukemia cells in culture (PMID: 22203728). 22203728
ALK R1275Q neuroblastoma sensitive CEP-28122 Preclinical - Cell culture Actionable In a preclinical study, CEP-28122 inhibited growth of neuroblastoma cells harboring ALK R1275Q in culture (PMID: 22203728). 22203728
ALK amp neuroblastoma sensitive CEP-28122 Preclinical - Cell culture Actionable In a preclinical study, CEP-28122 inhibited growth of ALK-amplified neuroblastoma cells in culture (PMID: 22203728). 22203728
ALK wild-type neuroblastoma resistant CEP-28122 Preclinical - Cell culture Actionable In a preclinical study, CEP-28122 did not inhibit growth of ALK wild-type neuroblastoma cells in culture (PMID: 22203728). 22203728
ALK negative colon carcinoma resistant CEP-28122 Preclinical - Cell line xenograft Actionable In a preclinical study, CEP-28122 did not inhibit tumor growth in cell line xenograft models of ALK-negative colon carcinoma (PMID: 22203728). 22203728
ALK negative lymphoma resistant CEP-28122 Preclinical - Cell culture Actionable In a preclinical study, CEP-28122 did not inhibit growth of ALK-negative lymphoma cells in culture (PMID: 22203728). 22203728
ALK negative lung non-small cell carcinoma resistant CEP-28122 Preclinical - Cell line xenograft Actionable In a preclinical study, ALK negative non-small cell lung carcinoma cells were resistant to CEP-28122 in culture and in cell line xenograft models (PMID: 22203728). 22203728
ALK F1174L neuroblastoma sensitive CEP-28122 Preclinical - Cell culture Actionable In a preclinical study, CEP-28122 inhibited growth of neuroblastoma cells harboring ALK F1174L in culture (PMID: 22203728). 22203728
NPM1-ALK anaplastic large cell lymphoma sensitive CEP-28122 Preclinical - Pdx & cell culture Actionable In a preclinical study, CEP-28122 inhibited Alk activation, resulting in growth inhibition in culture, and tumor regression in both cell line and patient-derived xenograft models of NPM1-ALK positive anaplastic large cell lymphoma (PMID: 22203728). 22203728