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Anaplastic lymphoma kinase (ALK), which belongs to the insulin receptor tyrosine kinase superfamily, plays an important role in nervous system development. Due to chromosomal translocations, point mutations, and gene amplification, constitutively activated ALK has been implicated in a variety of human cancers, including anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer, and neuroblastoma. We evaluated the anti-cancer activity of the ALK inhibitor KRCA-0008 using ALCL cell lines that express NPM (nucleophosmin)-ALK. KRCA-0008 strongly suppressed the proliferation and survival of NPM-ALK-positive ALCL cells. Additionally, it induced G0/G1 cell cycle arrest and apoptosis by blocking downstream signals including STAT3, Akt, and ERK1/2. Tumor growth was strongly suppressed in mice inoculated with Karpas-299 tumor xenografts and orally treated with KRCA-0008 (50 mg/kg, BID) for 2 weeks. Our results suggest that KRCA-0008 will be useful in further investigations of ALK signaling, and may provide therapeutic opportunities for NPM-ALK-positive ALCL patients.

The article focuses on a study which discussed the n-propyl tail effect to anaplastic lymphoma kinase (ALK) inhibition. Offered are information about nucleophosmin (NPM)-ALK fusion protein. Cited are several ALK inhibitors including the pyrimidine ALK inhibitors NVP-TAE684 and LDK378 or ceritinib. Also described is a general synthetic chemistry toward 2-anilino-4-(3,5-dicarboxamidespiperidine)-pyrimidines.

Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase ( ALK ) gene rearrangements invariably develop resistance to 2 nd -generation ALK inhibitors. Lorlatinib (PF-06463922) ( 6 ) is a 3 rd -generation macrocyclic ALK-TKI that demonstrates many advantages over 2 nd -generation ALK inhibitors. Lorlatinib has demonstrated decent kinase selectivity, promising pharmacokinetic profile, selective brain-penetration and strong antiproliferative activity in several ALK/ROS1-driven tumor models. The current review describes the activity spectrum, key events from discovery to clinical applications and the evidences that lorlatinib acts as an ALK/ROS1 inhibitor in clinical settings. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines is described and their structure–activity-relationship to anaplastic lymphoma kinase (ALK) is presented. KRCA-0008 is selective and potent to ALK and Ack1, and displays drug-like properties without hERG liability. KRCA-0008 demonstrates in vivo efficacy comparable to Crizotinib in xenograft mice model. [Copyright &y& Elsevier]