Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.4 (deaminase)
 5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Chloro-deoxyadenosine (CdA) is a new adenosine-deaminase (ADA) resistant purine analogue with high specificity for lymphoid cells. It was shown that CdA is very effective in hairy cell leukemia (HCL), refractory chronic lymphocytic leukemia and cutaneous T-cell lymphoma leading to lasting remissions in the majority of patients with HCL. We report the successful treatment of five patients with HCL at different stages of their disease using CdA, who were either previously untreated or had received interferon, splenectomy and deoxycoformycin (dCF), an ADA-inhibitor with high therapeutic efficacy in HCL. After one 7-day course of treatment, all patients reached remission. CdA was well tolerated and, only mild side effects such as skin rash, headache, fever, nausea were observed. Aplasia was pronounced in all instances with a slow recovery. The type of histomorphological procedure in preparing and evaluating bone marrow biopsies is emphasized to detect minimal residual infiltration by hairy cells.
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PMID:Successful treatment of patients with hairy cell leukemia (HCL) using a single cycle of 2-chloro-2'-deoxyadenosine (CdA). 790 21

Histone deacetylases have proven to be attractive novel targets for the treatment of cancer. The first inhibitor of histone deacetylases was approved for the treatment of cutaneous T-cell lymphoma in 2006. The identification of new lead structures with improved effectiveness and fewer side effects is necessary. This report investigates the mechanism of inhibition of a histone deacetylase-like amidohydrolase by stopped-flow and equilibrium titration techniques. The interaction between the inhibitor (E)-3-(furan-2-yl)-N-hydroxyacrylamide and the enzyme generates a fluorescence resonance energy transfer from the intrinsic tryptophan residues of the enzyme to the chromophore of the inhibitor. The apparent equilibrium binding constant was determined to be 1.9 muM. Several independent experimental results provide evidence of the existence of solely one HDAH conformer. The association kinetics showed two phases representing two unimolecular processes. Kinetic arguments and accurate investigation of the very fast time range suggest a fast pre-equilibrium, in which the inhibitor binds to the surface of the enzyme. In the next step, the first complex undergoes a conformational change that allows the inhibitor to translocate into the active site. Finally, the intermediate complex is stabilized by another conformational rearrangement. All kinetic data are in agreement with a reversible three-step mechanism and analyzed using a global fit, yielding the association constant of the pre-equilibrium (K(1) = 0.28 x 10(6) M(-1)) and the forward and reverse rate constants of the consecutive conformational changes (k(2) = 6.6 s(-1), k(-2) = 1.5 s(-1), k(3) = 0.8 s(-1), and k(-3) = 0.3 s(-1)).
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PMID:Mechanism of binding of the inhibitor (E)-3-(furan-2-yl)-N-hydroxyacrylamide to a histone deacetylase-like amidohydrolase. 2008 20

Inhibition of human histone deacetylases (HDACs) has emerged as a novel concept in the chemotherapeutic treatment of cancer. Two chemical entities, SAHA (ZOLINZA, Merck) and romidepsin (Istodax, Celgene) have been recently approved by the FDA as first-in-class drugs against cutaneous T-cell lymphoma. Clinical use of these drugs revealed several side effects including gastro-intestinal symptoms, fatigue, thrombocytopenia, thrombosis. Romidepsin is associated with an yet unresolved cardiotoxicity issue. A general hypothesis for the diminishment of unwanted adverse effects and an improved therapeutical window suggests the development of more isotype selective inhibitors. In this study the first time HDAC inhibitors with perfluorinated spacers between the zinc chelating moiety and the aromatic capping group were synthesized and tested against representatives of HDAC classes I, IIa and IIb. Competitive binding assays and a combined approach by using blind docking and molecular dynamics support binding of the perfluorinated analogs of SAHA to the active site of the HDAC-like amidohydrolase from Bordetella/Alcaligenes and presumably also to human HDACs. In contrast to the alkyl spacer of SAHA and derivatives, the perfluorinated alkyl spacer seems to contribute to or facilitate the induction of selectivity for class II, particularly class IIa, HDACs even though the overall potency of the perfluorinated SAHA analogs in this study against human HDACs remained still rather moderate in the micromolar range.
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PMID:Synthesis and biochemical analysis of 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-N-hydroxy-octanediamides as inhibitors of human histone deacetylases. 2218 79