The Discovery of Aurora Kinase Inhibitor by Multi-Docking-Based Virtual Screening

We report the discovery of aurora kinase inhibitor using the fragment-based virtual screening by multi-docking strategy. Among a number of fragments collected from eMololecules, we found four fragment molecules showing potent activity (>50% at 100 μM) against aurora kinase. Based on the explored fragment scaffold, we selected two compounds in our synthesized library and validated the biological activity against Aurora kinase.     

Targeting a Targeted Drug: An Approach Toward Hypoxia‐Activatable Tyrosine Kinase Inhibitor Prodrugs

Tyrosine kinase inhibitors (TKIs), which have revolutionized cancer therapy over the past 15 years, are limited in their clinical application due to serious side effects. Therefore, we converted two approved TKIs (sunitinib and erlotinib) into 2‐nitroimidazole‐based hypoxia‐activatable prodrugs. Kinetics studies showed very different stabilities over 24 h; however, fast reductive activation via E. coli nitroreductase could be confirmed for both panels. The anticancer activity and signaling inhibition of the compounds against various human cancer cell lines were evaluated in cell culture. These data, together with molecular docking simulations, revealed distinct differences in the impact of structural modifications on drug binding to the enzymes: whereas the catalytic pocket of the epidermal growth factor receptor (EGFR) accepted all new erlotinib derivatives, the vascular endothelial growth factor receptor (VEGFR)‐inhibitory potential in the case of the sunitinib prodrugs was dramatically diminished by derivatization. In line, hypoxia dependency of ERK signaling inhibition was observed with the sunitinib prodrugs, while oxygen levels had no impact on the activity of the erlotinib derivatives. Overall, proof of principle could be shown for this concept, and the results obtained are an important basis for the future development of tyrosine kinase inhibitor prodrugs.     

Identification,SAR Studies,and X‐ray Co‐crystallographic Analysis of a Novel Furanopyrimidine Aurora Kinase A Inhibitor

Herein we reveal a simple method for the identification of novel Aurora kinase A inhibitors through substructure searching of an in‐house compound library to select compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocyclic rings most frequently reported in kinase inhibitors were used as substructure queries to filter the in‐house compound library collection prior to testing. Five new series of Aurora kinase inhibitors were identified through this strategy, with IC₅₀ values ranging from ～300 nM to ～15 μM , by testing only 133 compounds from a database of ～125 000 compounds. Structure–activity relationship studies and X‐ray co‐crystallographic analysis of the most potent compound, a furanopyrimidine derivative with an IC₅₀ value of 309 nM toward Aurora kinase A, were carried out. The knowledge gained through these studies could help in the future design of potent Aurora kinase inhibitors.     

Discovery of 7‐Aryl‐Substituted (1,5‐Naphthyridin‐4‐yl)ureas as Aurora Kinase Inhibitors

As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7‐aryl‐1,5‐naphthyridin‐4‐yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5‐Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1‐cyclopropyl‐3‐[7‐(1‐methyl‐1H‐pyrazol‐4‐yl)‐1,5‐naphthyridin‐4‐yl]urea ( 49 ), displayed IC₅₀ values of 13 and 107 nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer‐related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents.     

Towards Dynamic Drug Design: Identification and Optimization of β‐Galactosidase Inhibitors from a Dynamic Hemithioacetal System

A discovery strategy relying on the identification of fragments through resolution of a constitutional dynamic system, coupled to subsequent static ligand design and optimization, is demonstrated. The strategic design and synthesis of the best molecular fragments identified from a dynamic hemithioacetal system into static ligand structures yielded a range of β‐galactosidase inhibitors. Two series of structures mimicking the hemithioacetal motif were envisaged: thioglycosides and C‐glycosides. Inhibition studies provided important structural information for the two groups, and 1‐thiobenzyl‐β‐D ‐galactopyranoside demonstrated the best inhibitory effects.     

Perspectives on Inhibiting β‐Amyloid Aggregation through Structure‐Based Drug Design

Targeting β‐amyloid (Aβ) remains the most desired strategy in Alzheimer’s disease (AD) drug discovery research. Many peptides that specifically target Aβ aggregates are known, encompassing efforts from both industrial and academic research settings. However, in clinical terms, not much success has been gained with peptide research; in turn, small drug‐like molecules are already globally recognized as showing promise as an alternate approach. Aβ aggregation inhibitors are the most important part of the multifunctional drug design regimen for treating AD. Unfortunately, rational drug design approaches with small molecules are still in the initial stages. Herein we highlight, update, and elaborate on the structural anatomy of Aβ and known Aβ aggregation inhibitors in hopes of helping to optimize their use in structure‐based drug design approaches toward inhibitors with greater specificity. Furthermore, we present the first review of efforts to target a previously uncharacterized region of acetylcholinesterase: the N‐terminal 7–20 sub‐region, which was experimentally elucidated to participate in Aβ aggregation and deposition.     

From Type I to Type II: Design,Synthesis, and Characterization of Potent Pyrazin‐2‐ones as DFG‐Out Inhibitors of PDGFRβ

Reversible protein kinase inhibitors that bind in the ATP cleft can be classified as type I or type II binders. Of these, type I inhibitors address the active form, whereas type II inhibitors typically lock the kinase in an inactive form. At the molecular level, the conformation of the flexible activation loop holding the key DFG motif controls access to the ATP site, thereby determining an active or inactive kinase state. Accordingly, type I and type II kinase inhibitors bind to so‐called DFG‐in or DFG‐out conformations, respectively. Based on our former study on highly selective platelet‐derived growth factor receptor β (PDGFRβ) pyrazin‐2‐one type I inhibitors, we expanded this scaffold toward the deep pocket, yielding the highly potent and effective type II inhibitor 5 (4‐[(4‐methylpiperazin‐1‐yl)methyl]‐N‐[3‐[[6‐oxo‐5‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrazin‐3‐yl]methyl]phenyl]benzamide). In vitro characterization, including selectivity panel data from activity‐based assays (300 kinases) and affinity‐based assays (97 kinases) of these PDGFRβ type I ( 1 ; 5‐(4‐hydroxy‐3‐methoxy‐phenyl)‐3‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrazin‐2‐one) and II ( 5 ) inhibitors showing the same pyrazin‐2‐one chemotype are compared. Implications are discussed regarding the data for selectivity and efficacy of type I and type II ligands.     

Truncation and Optimisation of Peptide Inhibitors of Cyclin‐Dependent Kinase 2‐Cyclin A Through Structure‐Guided Design

Peptides that inhibit cyclin‐dependent kinase 2 by blocking the macromolecular substrate recruitment site of cyclin A were simplified, for example, by replacement of dipeptide units with β‐amino acids. The smallest inhibitor retaining activity was a tripeptide, whose binding mode was confirmed by X‐ray crystallography. This result suggests that nonpeptidic cyclin groove inhibitors may be feasible therapeutic agents.

     

Structure‐Based Design of New KSP‐Eg5 Inhibitors Assisted by a Targeted Multicomponent Reaction

An integrated multidisciplinary approach that combined structure‐based drug design, multicomponent reaction synthetic approaches and functional characterization in enzymatic and cell assays led to the discovery of new kinesin spindle protein (KSP) inhibitors with antiproliferative activity. A focused library of new benzimidazoles obtained by a Ugi+Boc removal/cyclization reaction sequence generated low‐micromolar‐range KSP inhibitors as promising anticancer prototypes. The design and functional studies of the new chemotypes were assessed by computational modeling and molecular biology techniques. The most active compounds— 20 (IC₅₀=1.49 μM , EC₅₀=3.63 μM ) and 22 (IC₅₀=1.37 μM , EC₅₀=6.90 μM )—were synthesized with high efficiency by taking advantage of the multicomponent reactions.     

The Inhibitory Properties of a Novel,Selective LMTK3 Kinase Inhibitor

Recently, the oncogenic role of lemur tyrosine kinase 3 (LMTK3) has been well established in different tumor types, highlighting it as a viable therapeutic target. In the present study, using in vitro and cell-based assays coupled with biophysical analyses, we identify a highly selective small molecule LMTK3 inhibitor, namely C36. Biochemical/biophysical and cellular studies revealed that C36 displays a high in vitro selectivity profile and provides notable therapeutic effect when tested in the National Cancer Institute (NCI)-60 cancer cell line panel. We also report the binding affinity between LMTK3 and C36 as demonstrated via microscale thermophoresis (MST). In addition, C36 exhibits a mixed-type inhibition against LMTK3, consistent with the inhibitor overlapping with both the adenosine 5′-triphosphate (ATP)- and substrate-binding sites. Treatment of different breast cancer cell lines with C36 led to decreased proliferation and increased apoptosis, further reinforcing the prospective value of LMTK3 inhibitors for cancer therapy.     

Synthesis, 3D‐QSAR,and Structural Modeling of Benzolactam Derivatives with Binding Affinity for the D2 and D3 Receptors

A series of 37 benzolactam derivatives were synthesized, and their respective affinities for the dopamine D₂ and D₃ receptors evaluated. The relationships between structures and binding affinities were investigated using both ligand‐based (3D‐QSAR) and receptor‐based methods. The results revealed the importance of diverse structural features in explaining the differences in the observed affinities, such as the location of the benzolactam carbonyl oxygen, or the overall length of the compounds. The optimal values for such ligand properties are slightly different for the D₂ and D₃ receptors, even though the binding sites present a very high degree of homology. We explain these differences by the presence of a hydrogen bond network in the D₂ receptor which is absent in the D₃ receptor and limits the dimensions of the binding pocket, causing residues in helix 7 to become less accessible. The implications of these results for the design of more potent and selective benzolactam derivatives are presented and discussed.