Exploration of the HDAC2 foot pocket: Synthesis and SAR of substituted N-(2-aminophenyl)benzamides

Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

“…The PfHADC1 amino acid sequence (http://www.uniprot.org; accession number Q7K6A1) was used in a BLAST (2) search of the Protein Data Bank (PDB) (14) to identify crystal structures of proteins with similar sequences, giving human HDAC2 (PDB accession no. 3max; resolution of 2.05 Å; 63% identity) (16) and HDAC8 (PDB accession no. 1t64; resolution of 1.90 Å; 41% identity).…”

New and emerging HDAC inhibitors for cancer treatment

“…The recruitment of HDAC1-, HDAC2-, and/ or HDAC3-containing transcription regulatory complexes to leukemogenic fusion proteins indicates class I-specific agents may be particularly suited to the treatment of tumors driven by discrete oncogenic proteins. The pharmacologic development of class Ispecific or isoform-specific HDACis is currently underway, aided by clarification of the HDAC2 catalytic site following cocrystallization (65). Chemical modeling based on the HDAC2 crystal structure has allowed the generation of a series HDAC2-specific benzamides, and the inclusion of a sulfhydryl group may allow specific inhibition of HDAC1 (65,66).…”

“…The pharmacologic development of class Ispecific or isoform-specific HDACis is currently underway, aided by clarification of the HDAC2 catalytic site following cocrystallization (65). Chemical modeling based on the HDAC2 crystal structure has allowed the generation of a series HDAC2-specific benzamides, and the inclusion of a sulfhydryl group may allow specific inhibition of HDAC1 (65,66). Given the close sequence homology and observed functional redundancy mechanisms and compensatory expression relationships that occur between HDAC1 and -2, it will be of interest to determine whether these compounds confer different antitumor effects.…”

Synthesis of 1,2-benzisoxazole tethered 1,2,3-triazoles that exhibit anticancer activity in acute myeloid leukemia cell lines by inhibiting histone deacetylases, and inducing p21 and tubulin acetylation

“…All compounds show a high degree of shape complementarity to the binding site of HDAC6, forming multiple molecular interactions in the hydrophobic region as well as a hydrogen bond to the phenol side-chain of Tyr-782. Compared to the co-crystal structures of HDAC2 inhibitors N-(2-aminophenyl)benzamide (PDB: 3MAX) 52 and the prototypical inhibitor suberanilohydroxamic acid SAHA (PDB: 4LXZ), 53 similar regions of the binding site are explored including the HDAC foot pocket. The point of variation explored in our series is predicted to occupy a solvent-exposed region, thus explaining the observed rather flat structure-activity relationship.…”