The design and synthesis of 5- and 6-isoxazolylbenzimidazoles as selective inhibitors of the BET bromodomains

Abstract

Simple 1-substituted 5-and 6-isoxazolyl-benzimidazoles have been shown to be potent inhibitors of the BET bromodomains with selectivity over the related bromodomain of CBP. The reported inhibitors were prepared from simple starting materials in two steps followed by separation of the regioisomers or regioselectively in three steps.Bromodomains are discrete protein domains that selectively recognize acetyl lysine in proteins. 1 There are 61 bromodomains in proteins that have a variety of functions including histone acetyl transferases such as CBP (cyclic AMP response element-binding protein, binding protein), methyl transferases, transcriptional regulators such as BRD4 (bromodomain-containing protein 4) and chromatin remodelling complexes. 2 The BET family of bromodomain containing proteins is comprised of BRDT, BRD2, BRD3 and BRD4 each of which has two bromodomains that bind to acetylated histone tails. 3 Recently BET inhibitors have been shown to have potential for use in inflammatory disease, atherosclerosis, NUT midline carcinoma, acute leukaemia and lymphoma. [4][5][6][7][8][9] Triazoloazepines such as (+)-JQ1 1, iBET762 (structure not shown) and isoxazoles such as compound 2 have been identified as potent BET inhibitors (Fig. 1). 4,9,10 Since then, a number of other templates incorporating the privileged isoxazole moiety such as in compounds 3 and 4 have been identified by researchers in the EpiNova group at GlaxoSmithKline. 6,11,12 As most known BET inhibitors are complex stereogenic molecules it would be advantageous to find simple, rapidly accessible inhibitors that would be selective † This article is part of a MedChemComm 'New Talents' issue highlighting the work of outstanding rising scientists in medicinal chemistry research. It was thought that fusing a 5-membered ring to the 4-aryl-3,5-dimethylisoxazole moiety of compound 2 (ref. 10) would give access to previously unexploited substitution patterns in known isoxazole-containing bromodomain inhibitors. Simple 5,6-bicyclic bromides 5a-c were transformed into isoxazoles by either direct arylation of 3,5-dimethylisoxazole or Suzuki reaction of the isoxazolylboronic acid to give compounds 6-8 (Scheme 1). 10,13 When tested in an AlphaScreen® assay using isolated bromodomains, compounds 6 and 7 were modest inhibitors of the first bromodomain of BRD4 (BRD4(1)) with no affinity for the CBP bromodomain whereas compound 8 had comparable affinity for both bromodomains (Table 1). 14 The indanone 6 presented an attractive intermediate for further derivitization (Scheme 2). Reduction to the racemic indanol followed by alkylation with benzyl bromide or 2-bromomethyl quinolone gave compounds 9 and 10. The amines 10-14 were prepared by S N 1 alkylation of the indanol with 3-bromo-n-propanol followed by bromide substitution. The basic centres of varying pK a in compounds 10-14 were designed with the potential to interact with an acidic residue on the edge of the BRD4(1) binding pocket, D145.Addition of an O-benzyl group in compound 9 did not increase the affi...

Targeting BET Bromodomains for Cancer Treatment

“…The dimethylisoxazole chemotype was identified by different groups as a BET inhibitor using fragmentbased approaches [60,[107][108][109]. The quinoline dimethylisoxazole I-BET151 is the best characterized substance of this group [88].…”

Isoxazole‐Derived Amino Acids are Bromodomain‐Binding Acetyl‐Lysine Mimics: Incorporation into Histone H4 Peptides and Histone H3

“…[18] During the development of ligands for the bromodomain and extra-terminal domain (BET) family of bromodomaincontaining proteins (BCPs), we identified the 3,5-dimethylisoxazole (DMI) moiety as an effective KAc mimic. [29][30][31] Sharp et al subsequently showed that the DMI moiety is most potent based on ac omparison of KAc mimics. [32] Our analysis of the ChEMBL data base (https://www.ebi.ac.uk/ chembl/) revealed that 4-phenyl-3,5-dimethylisoxazole (1; Figure 1A)possesses the highest binding efficiency index and surface efficiencyi ndex [33] for the BET BCPs,B RD2 and BRD4.…”

BET inhibition as a new strategy for the treatment of gastric cancer

“…PNZ5 was developed as the result of a structure-based lead optimisation program. Dihydroindene S1 was identified as a ligand against BRD4(1) (pIC 50 5.9) [30]. Investigation of the co-crystal structure of S1 with BRD4(1) [PDB ID 4GPJ] identified a number of positions for potential optimisation: addition of a carbonyl group at C-3 was envisaged to benefit from hydrogen-bonds (H-bonds) to a network of conserved water molecules; replacement of C-2 with a nitrogen would minimise interactions in the narrow ZA channel of BRD4(1) and N -substitution could provide further binding interactions with the protein; and alternative substitution of the hydroxyl at C-1 would provide a handle for further optimisation.…”