ALK inhibitors of bis-ortho-alkoxy-para-piperazinesubstituted-pyrimidines and -triazines for cancer treatment.
Syntheses of various bis-ortho-alkoxy-para-piperazineanilino-pyrimidines and -triazines of KRCA-0008 analogs are described and their structure-activity-relationship to anaplastic lymphoma kinase (ALK) is discussed. 5-trifluoromethyl-2,4-pyrimidine analog (2) seems to be most potent in both biochemical and cellular assay in this study, however it shows inferior mice xenograft activity to Crizotinib presumably due to its sub-optimal PK parameters. 4,6-disubstituted pyrimidine and 2,4-disubstituted triazine derivatives of KRCA-0008 are less potent or inactive to ALK wt., and this observation is explained with their molecular modeling compared to KRCA-0008.
Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Taejon, 305-600, Republic of Korea.
Hyeon Ji
HJ
Lee
Muhammad
M
Latif
Hyeonjeong
H
Choe
Imran
I
Ali
Heung Kyoung
HK
Lee
Eun Hye
EH
Yang
Jeong In
JI
Yun
Chong Hak
CH
Chae
Jae-Kyung
JK
Jung
Hyoung Rae
HR
Kim
Chong Ock
CO
Lee
Chi Hoon
CH
Park
Kwangho
K
Lee
D019943:Amino Acid Substitution; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006207:Half-Life; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C000597555:1,1'-((((5-(trifluoromethyl)pyrimidine-2,4-diyl)bis(azanediyl))bis(3-methoxy-4,1-phenylene))bis(piperazine-4,1-diyl))bis(ethan-1-one); D000970:Antineoplastic Agents; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014227:Triazines; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases