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1.
Nucleic Acids Res ; 41(12): 6034-44, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23630318

RESUMO

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. PK7088 increased the amount of folded mutant protein with wild-type conformation, as monitored by immunofluorescence, and restored its transcriptional functions. It induced p53-Y220C-dependent growth inhibition, cell-cycle arrest and apoptosis. Most notably, PK7088 increased the expression levels of p21 and the proapoptotic NOXA protein. PK7088 worked synergistically with Nutlin-3 on up-regulating p21 expression, whereas Nutlin-3 on its own had no effect, consistent with its mechanism of action. PK7088 also restored non-transcriptional apoptotic functions of p53 by triggering nuclear export of BAX to the mitochondria. We suggest a set of criteria for assigning activation of p53.


Assuntos
Antineoplásicos/farmacologia , Mutação , Pirazóis/farmacologia , Pirróis/farmacologia , Proteína Supressora de Tumor p53/efeitos dos fármacos , Antineoplásicos/química , Apoptose , Caspase 3/metabolismo , Caspase 7/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Genes p53 , Humanos , Conformação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Pirazóis/química , Pirróis/química , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo
2.
Bioorg Med Chem Lett ; 23(11): 3346-8, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23591111

RESUMO

We have synthesized a ß-cyclodextrin (ßCD)-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. However, compound 3 displayed no cellular activity.


Assuntos
Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Proteínas Repressoras/química , beta-Ciclodextrinas/química , Sítios de Ligação , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Simulação de Acoplamento Molecular , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Proteínas Repressoras/metabolismo , Vorinostat , Zinco/química , beta-Ciclodextrinas/metabolismo
3.
Chem Sci ; 7(3): 2322-2330, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29910922

RESUMO

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. The PHIP(2) binding site contains a threonine in place of asparagine, and solution screening have yielded no convincing hits. We have overcome this hurdle by combining the sensitivity of X-ray crystallography, used as the primary fragment screen, with a strategy for rapid follow-up synthesis using a chemically-poised fragment library, which allows hits to be readily modified by parallel chemistry both peripherally and in the core. Our approach yielded the first reported hit compounds of PHIP(2) with measurable IC50 values by an AlphaScreen competition assay. The follow-up libraries of four poised fragment hits improved potency into the sub-mM range while showing good ligand efficiency and detailed structural data.

4.
Chem Commun (Camb) ; 48(82): 10192-4, 2012 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-22911326

RESUMO

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.


Assuntos
Cobalto/química , Compostos Organometálicos/síntese química , Cristalografia por Raios X , Ciclização , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/química , Oxirredução , Estereoisomerismo
5.
Metallomics ; 3(6): 600-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21359402
6.
ACS Med Chem Lett ; 2(5): 358-362, 2011 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-21572592

RESUMO

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, 1.41 (0.15); 7, 1.36 (0.16). Thereafter, a small library of related JAHA analogues has been synthesized, and preliminary SAR studies are presented. IC(50) values as low as 90 pM toward HDAC6 (class IIb) have been determined, highlighting the excellent potential of JAHAs as bioinorganic probes.

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