Identification of E2F-1/Cyclin A antagonists.
A simple method for the synthesis of a rationally designed (S,S)-[Pro-Leu]-spirolactam scaffold is described. This was expanded to a small biased library of compounds mimicking the 'ZRXL' motif in order to identify E2F-1/Cyclin A antagonists. The synthesized compounds were evaluated in an E2F-1/Cyclin A binding assay and moderately active analogues were identified. In addition, the critical roles of Phe, Leu, Lys, and Arg residues of the identified motif were determined.
Sharma
S K
SK
Oncology Department, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA. sushil.sharma@pharma.novartis.com
Ramsey
T M
TM
Chen
Y N
YN
Chen
W
W
Martin
M S
MS
Clune
K
K
Sabio
M
M
Bair
K W
KW
D000595:Amino Acid Sequence; D001665:Binding Sites; D001671:Biochemistry / Q000379:methods; D018797:Cell Cycle Proteins; D020650:Combinatorial Chemistry Techniques; D017124:Conserved Sequence; D019925:Cyclin A / Q000037:antagonists & inhibitors*; D004268:DNA-Binding Proteins; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004797:Enzyme-Linked Immunosorbent Assay; D020128:Inhibitory Concentration 50; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
D018797:Cell Cycle Proteins; D019925:Cyclin A; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D019151:Peptide Library; D010455:Peptides; D014157:Transcription Factors