109093-31-4Relevant articles and documents
The relevance of Ki calculation for bi-substrate enzymes illustrated by kinetic evaluation of a novel lysine (K) acetyltransferase 8 inhibitor
Wapenaar, Hannah,van den Bosch, Thea,Leus, Niek G.J.,van der Wouden, Petra E.,Eleftheriadis, Nikolaos,Hermans, Jos,Hailu, Gebremedhin Solomon,Rotili, Dante,Mai, Antonello,D?mling, Alexander,Bischoff, Rainer,Haisma, Hidde J.,Dekker, Frank J.
, p. 480 - 486 (2017)
Histone acetyltransferases (HATs) are important mediators of epigenetic post-translational modifications of histones that play important roles in health and disease. A disturbance of these modifications can result in disease states, such as cancer or inflammatory diseases. Inhibitors of HATs (HATi) such as lysine (K) acetyltransferase 8 (KAT8), could be used to study the epigenetic processes in diseases related to these enzymes or to investigate HATs as therapeutic targets. However, the development of HATi is challenged by the difficulties in kinetic characterization of HAT enzymes and their inhibitors to enable calculation of a reproducible inhibitory potency. In this study, a fragment screening approach was used, enabling identification of 4-amino-1-naphthol, which potently inhibited KAT8. The inhibitor was investigated for enzyme inhibition using kinetic and calorimetric binding studies. This allowed for calculation of the Ki values for both the free enzyme as well as the acetylated intermediate. Importantly, it revealed a striking difference in binding affinity between the acetylated enzyme and the free enzyme, which could not be revealed by the IC50 value. This shows that kinetic characterization of inhibitors and calculation of Ki values is crucial for determining the binding constants of HAT inhibitors. We anticipate that more comprehensive characterization of enzyme inhibition, as described here, is needed to advance the field of HAT inhibitors.
1,2-Naphthoquinone-based Derivatives and and Methods for Preparing them
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Paragraph 0659; 0660; 0665-0667, (2016/11/24)
The present invention relates to a compound represented by chemical formula (1), a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug, a tautomer, an enantiomer, or a pharmaceutically acceptable diastereomer thereof, a preparing method thereof, and a medical composition having a treating or preventing effect of metabolic diseases containing the same. Here, R_1 to R_3, and X_1 to X_6 are the same as defined in a first claim.COPYRIGHT KIPO 2015
3-substituted-N-(4-hydroxynaphthalen-1-yl)arylsulfonamides as a novel class of selective Mcl-1 inhibitors: Structure-based design, synthesis, SAR, and biological evaluation
Abulwerdi, Fardokht A.,Liao, Chenzhong,Mady, Ahmed S.,Gavin, Jordan,Shen, Chenxi,Cierpicki, Tomasz,Stuckey, Jeanne A.,Showalter, H.D. Hollis,Nikolovska-Coleska, Zaneta
supporting information, p. 4111 - 4133 (2014/06/09)
Mcl-1, an antiapoptotic member of the Bcl-2 family of proteins, is a validated and attractive target for cancer therapy. Overexpression of Mcl-1 in many cancers results in disease progression and resistance to current chemotherapeutics. Utilizing high-throughput screening, compound 1 was identified as a selective Mcl-1 inhibitor and its binding to the BH3 binding groove of Mcl-1 was confirmed by several different, but complementary, biochemical and biophysical assays. Guided by structure-based drug design and supported by NMR experiments, comprehensive SAR studies were undertaken and a potent and selective inhibitor, compound 21, was designed which binds to Mcl-1 with a Ki of 180 nM. Biological characterization of 21 showed that it disrupts the interaction of endogenous Mcl-1 and biotinylated Noxa-BH3 peptide, causes cell death through a Bak/Bax-dependent mechanism, and selectively sensitizes Eμ-myc lymphomas overexpressing Mcl-1, but not Eμ-myc lymphoma cells overexpressing Bcl-2. Treatment of human leukemic cell lines with compound 21 resulted in cell death through activation of caspase-3 and induction of apoptosis.
