A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain.

Research into the chemical biology of bromodomains has been driven by the development of acetyl-lysine mimetics. The ligands are typically anchored by binding to a highly conserved asparagine residue. Atypical bromodomains, for which the asparagine is mutated, have thus far proven elusive targets, including PHIP(2) whose parent protein, PHIP, has been linked to disease progression in diabetes and cancers.

Small molecule induced reactivation of mutant p53 in cancer cells.

The p53 cancer mutant Y220C is an excellent paradigm for rescuing the function of conformationally unstable p53 mutants because it has a unique surface crevice that can be targeted by small-molecule stabilizers. Here, we have identified a compound, PK7088, which is active in vitro: PK7088 bound to the mutant with a dissociation constant of 140 μM and raised its melting temperature, and we have determined the binding mode of a close structural analogue by X-ray crystallography. We showed that PK7088 is biologically active in cancer cells carrying the Y220C mutant by a battery of tests.

A cyclodextrin-capped histone deacetylase inhibitor.

We have synthesized a β-cyclodextrin (βCD)-capped histone deacetylase (HDAC) inhibitor 3 containing an alkyl linker and a zinc-binding hydroxamic acid motif. Biological evaluation (HDAC inhibition studies) of 3 enabled us to establish the effect of replacing an aryl cap (in SAHA (vorinostat,)) 1 by a large saccharidic scaffold "cap". HDAC inhibition was observed for 3, to a lesser extent than SAHA, and rationalized by molecular docking into the active site of HDAC8.

Diastereoselective synthesis of half-sandwich chiral-at-metal cobaltacycles by oxidative cyclisation.

Reaction of chiral ester linked diynes with chlorotris(triphenylphosphine)cobalt(I) and sodium cyclopentadienide gave (η(5)-cyclopentadienyl)(triphenylphosphine) cobaltacyclopentadiene complexes as single chiral-at-metal diastereoisomers, including a non-racemic example synthesised in three steps from (S)-3-butyn-2-ol.

Synthesis and Biological Evaluation of JAHAs: Ferrocene-Based Histone Deacetylase Inhibitors.

N(1)-Hydroxy-N(8)-ferrocenyloctanediamide, JAHA (7), an organometallic analogue of SAHA containing a ferrocenyl group as a phenyl bioisostere, displays nanomolar inhibition of class I HDACs, excellent selectivity over class IIa HDACs, and anticancer action in intact cells (IC(50) = 2.4 μM, MCF7 cell line). Molecular docking studies of 7 in HDAC8 (a,b) suggested that the ferrocenyl moiety in 7 can overlap with the aryl cap of SAHA and should display similar HDAC inhibition, which was borne out in an in vitro assay (IC(50) values against HDAC8 (μM, SD in parentheses): SAHA, 1.

Synthesis and evaluation of metallocene containing methylidene-1,3-dihydro-2H-indol-2-ones as kinase inhibitors.

(E)- and (Z)-3-Ferrocenylmethylidene-1,3-dihydro-2H-indol-2-ones 1 have been structurally modified in order to explore SAR against a range of kinases. Of note is the submicromolar to low micromolar inhibition of DYRK3 and 4 by a number of complexes. Screening using Xenopus embryos showed some of the compounds to have potent antiangiogenisis activity.