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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	11	3	2012 Mar	670-9	Mol Cancer Ther

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	9	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CEP-28122			ALK Inhibitor 32	CEP-28122 is a small molecule inhibitor of ALK that inhibits growth of ALK-positive tumors (PMID: 22203728).

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
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 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
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 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 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
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 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