Abstract
Structure-based-design studies, with the crystal structure of the HOXB1-PBX1/DNA transcription factor complex, were used to identify 1,4-disubstituted naphthalenes as potential antagonists. An initial library of 32 analogs was synthesized, two of which were found to be more potent than the reported activity for a 12 amino acid peptide antagonist. Antagonists were also identified of the related BRN1/DNA and BRN2/DNA transcription factor complexes indicating that a 1,4-disubstituted naphthalene may be a privileged scaffold for preparing screening libraries targeting this family of transcription factor complexes.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Crystallography, X-Ray
-
DNA / antagonists & inhibitors
-
DNA-Binding Proteins / antagonists & inhibitors*
-
DNA-Binding Proteins / chemistry
-
Homeodomain Proteins / antagonists & inhibitors*
-
Homeodomain Proteins / chemistry
-
Humans
-
Kinetics
-
Models, Molecular
-
Naphthalenes / chemical synthesis
-
Naphthalenes / chemistry
-
Naphthalenes / pharmacology*
-
Pre-B-Cell Leukemia Transcription Factor 1
-
Proto-Oncogene Proteins / antagonists & inhibitors*
-
Proto-Oncogene Proteins / chemistry
-
Transcription Factors / antagonists & inhibitors*
Substances
-
DNA-Binding Proteins
-
HOXB1 homeodomain protein
-
Homeodomain Proteins
-
Naphthalenes
-
Pre-B-Cell Leukemia Transcription Factor 1
-
Proto-Oncogene Proteins
-
Transcription Factors
-
PBX1 protein, human
-
DNA