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1.
Eur J Med Chem ; 227: 113948, 2022 Jan 05.
Article in English | MEDLINE | ID: mdl-34742017

ABSTRACT

DYRK1A phosphorylates proteins involved in neurological disorders in an intermolecular manner. Meanwhile, during the protein folding process of DYRK1A, a transitional folding intermediate catalyzes the intramolecular autophosphorylation required for the "one-off" inceptive activation and stabilization. In our previous study, a small molecule termed FINDY (1) was identified, which inhibits the folding intermediate-catalyzed intramolecular autophosphorylation of DYRK1A but not the folded state-catalyzed intermolecular phosphorylation. However, the structural features of FINDY (1) responsible for this intermediate-selective inhibition remain elusive. In this study, structural derivatives of FINDY (1) were designed and synthesized according to its predicted binding mode in the ATP pocket of DYRK1A. Quantitative structure-activity relationship (QSAR) of the derivatives revealed that the selectivity against the folding intermediate is determined by steric hindrance between the bulky hydrophobic moiety of the derivatives and the entrance to the pocket. In addition, a potent derivative 3 was identified, which inhibited the folding intermediate more strongly than FINDY (1); it was designated as dp-FINDY. Although dp-FINDY (3) did not inhibit the folded state, as well as FINDY (1), it inhibited the intramolecular autophosphorylation of DYRK1A in an in vitro cell-free protein synthesis assay. Furthermore, dp-FINDY (3) destabilized endogenous DYRK1A in HEK293 cells. This study provides structural insights into the folding intermediate-selective inhibition of DYRK1A and expands the chemical options for the design of a kinase inhibitor.


Subject(s)
Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Thiazoles/pharmacology , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship , Thiazoles/chemistry , Dyrk Kinases
2.
Org Lett ; 22(16): 6687-6691, 2020 08 21.
Article in English | MEDLINE | ID: mdl-32806152

ABSTRACT

An efficient transformation of dibenzoxaborins to dibenzofurans by deborylative ring contraction was achieved under mild conditions using a copper catalyst. The method showed a broad substrate scope enabling the preparation of various dibenzofurans, including those bearing a functional group. The ready availability of various dibenzoxaborins enhances the utility of this method, as demonstrated by the regiodivergent synthesis of dibenzofurans.

3.
Proc Natl Acad Sci U S A ; 114(38): 10268-10273, 2017 09 19.
Article in English | MEDLINE | ID: mdl-28874550

ABSTRACT

Down syndrome (DS) caused by trisomy of chromosome 21 is the most common genetic cause of intellectual disability. Although the prenatal diagnosis of DS has become feasible, there are no therapies available for the rescue of DS-related neurocognitive impairment. A growth inducer newly identified in our screen of neural stem cells (NSCs) has potent inhibitory activity against dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) and was found to rescue proliferative deficits in Ts65Dn-derived neurospheres and human NSCs derived from individuals with DS. The oral administration of this compound, named ALGERNON (altered generation of neurons), restored NSC proliferation in murine models of DS and increased the number of newborn neurons. Moreover, administration of ALGERNON to pregnant dams rescued aberrant cortical formation in DS mouse embryos and prevented the development of abnormal behaviors in DS offspring. These data suggest that the neurogenic phenotype of DS can be prevented by ALGERNON prenatal therapy.


Subject(s)
Down Syndrome/drug therapy , Fetal Therapies , Neural Stem Cells/drug effects , Neurogenesis/drug effects , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/embryology , Cerebral Cortex/pathology , Cognition/drug effects , Cyclin D1/metabolism , Dentate Gyrus/drug effects , Dentate Gyrus/pathology , Down Syndrome/pathology , Down Syndrome/psychology , Female , HEK293 Cells , Humans , Learning/drug effects , Male , Mice , Neural Stem Cells/pathology , Pregnancy , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Dyrk Kinases
4.
Phys Chem Chem Phys ; 19(39): 26926-26933, 2017 Oct 11.
Article in English | MEDLINE | ID: mdl-28956039

ABSTRACT

In this study, three reaction mechanisms of a benzyne-nickel (Ni) complex ([Ni(C6H4)(dcpe)]) with iodomethane during the methylation process were investigated, namely (a) SN2 reaction of the benzyne-Ni complex with iodomethane, (b) concerted σ-bond metathesis during the bond breaking/forming processes, and (c) oxidative addition of iodomethane to the Ni-center and the subsequent reductive elimination process. DFT calculations revealed that the reaction barrier of the SN2 reaction is slightly lower than those of the other mechanisms. The results of orbital analyses suggest that [Ni(C6H4)(dcpe)] forms a metallacycle structure between benzyne and the NiII (3d8) center instead of the η2-structure with the Ni0 (3d10) center. The metallacycle structures became inappropriate as the intermediates of oxidative addition in the formation of the NiII-Me bond, avoiding further oxidation to the high-valent NiIV. The high free energy along σ-bond metathesis was generated from the steric hindrance, thus invoking methylation and Ni-I bond formation concertedly.

5.
Org Lett ; 18(21): 5600-5603, 2016 11 04.
Article in English | MEDLINE | ID: mdl-27748111

ABSTRACT

A facile method for preparing diverse aryne-nickel complexes from readily synthesized ortho-borylaryl triflates is described. Exploratory synthetic applications, including the synthesis of 1,2-difunctionalized arenes, based on the nucleophilic character of the aryne-nickel complexes are also demonstrated.

6.
Nat Commun ; 7: 11391, 2016 Apr 22.
Article in English | MEDLINE | ID: mdl-27102360

ABSTRACT

Autophosphorylation of amino-acid residues is part of the folding process of various protein kinases. Conventional chemical screening of mature kinases has missed inhibitors that selectively interfere with the folding process. Here we report a cell-based assay that evaluates inhibition of a kinase at a transitional state during the folding process and identify a folding intermediate-selective inhibitor of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), which we refer to as FINDY. FINDY suppresses intramolecular autophosphorylation of Ser97 in DYRK1A in cultured cells, leading to its degradation, but does not inhibit substrate phosphorylation catalysed by the mature kinase. FINDY also suppresses Ser97 autophosphorylation of recombinant DYRK1A, suggesting direct inhibition, and shows high selectivity for DYRK1A over other DYRK family members. In addition, FINDY rescues DYRK1A-induced developmental malformations in Xenopus laevis embryos. Our study demonstrates that transitional folding intermediates of protein kinases can be targeted by small molecules, and paves the way for developing novel types of kinase inhibitors.


Subject(s)
Biological Assay , Protein Folding/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Thiazoles/pharmacology , Amino Acid Sequence , Animals , Biomarkers/metabolism , Cantharidin/pharmacology , Embryo, Nonmammalian , Gene Expression Regulation, Developmental , HEK293 Cells , Humans , Marine Toxins , Molecular Sequence Data , Okadaic Acid/pharmacology , Oxazoles/pharmacology , Phosphorylation/drug effects , Plasmids/chemistry , Plasmids/metabolism , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Recombinant Proteins , Sequence Alignment , Thiazoles/chemistry , Transfection , Xenopus laevis/embryology , Dyrk Kinases
7.
Sci Rep ; 5: 12728, 2015 Aug 03.
Article in English | MEDLINE | ID: mdl-26234946

ABSTRACT

The protein kinase family includes attractive targets for drug development. Methods for screening of kinase inhibitors remain largely limited to in vitro catalytic assays. It has been shown that ATP-competitive inhibitors antagonize interaction between the target kinase and kinase-specific co-chaperone CDC37 in living cells. Here we show a cell-based method to screen kinase inhibitors using fusion protein of CDC37 with a mutated catalytic 19-kDa component of Oplophorus luciferase, nanoKAZ (CDC37-nanoKAZ). A dual-specificity kinase DYRK1A, an importance of which has been highlighted in Alzheimer's disease, was targeted in this study. We established 293T cells stably expressing CDC37-nanoKAZ, and analyzed interaction between CDC37-nanoKAZ and DYRK1A. We revealed that DYRK1A interacted with CDC37-nanoKAZ. Importantly, point mutations that affect autophosphorylation strengthened the interaction, thus improving signal/noise ratio of the interaction relative to non-specific binding of CDC37-nanoKAZ. This high signal/noise ratio enabled screening of chemical library that resulted in identification of a potent inhibitor of DYRK1A, named CaNDY. CaNDY induced selective degradation of DYRK1A, and inhibited catalytic activity of recombinant DYRK1A with IC50 value of 7.9 nM by competing with ATP. This method based on a mutant target kinase and a bioluminescence-eliciting co-chaperone CDC37 could be applicable to evaluation and development of inhibitors targeting other kinases.


Subject(s)
Cell Cycle Proteins/genetics , Chaperonins/genetics , Drug Evaluation, Preclinical/methods , Luciferases/genetics , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Benzofurans/pharmacology , Cell Cycle Proteins/metabolism , Chaperonins/metabolism , HEK293 Cells , HSP90 Heat-Shock Proteins/genetics , HSP90 Heat-Shock Proteins/metabolism , Humans , Luciferases/metabolism , Molecular Chaperones/genetics , Mutation , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Small Molecule Libraries/pharmacology , Thiazolidines/pharmacology , Triazoles/pharmacology , Dyrk Kinases
8.
Bioorg Med Chem ; 23(15): 4434-4441, 2015 Aug 01.
Article in English | MEDLINE | ID: mdl-26145823

ABSTRACT

Dysregulation of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) has been demonstrated in several pathological conditions, including Alzheimer's disease and cancer progression. It has been recently reported that a gain of function-mutation in the human DYRK1B gene exacerbates metabolic syndrome by enhancing obesity. In the previous study, we developed an inhibitor of DYRK family kinases (INDY) and demonstrated that INDY suppresses the pathological phenotypes induced by overexpression of DYRK1A or DYRK1B in cellular and animal models. In this study, we designed and synthesized a novel inhibitor of DYRK family kinases based on the crystal structure of the DYRK1A/INDY complex by replacing the phenol group of INDY with dibenzofuran to produce a derivative, named BINDY. This compound exhibited potent and selective inhibitory activity toward DYRK family kinases in an in vitro assay. Furthermore, treatment of 3T3-L1 pre-adipocytes with BINDY hampered adipogenesis by suppressing gene expression of the critical transcription factors PPARγ and C/EBPα. This study indicates the possibility of BINDY as a potential drug for metabolic syndrome.


Subject(s)
Benzofurans/chemical synthesis , Benzothiazoles/chemical synthesis , Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , 3T3-L1 Cells , Adipogenesis/drug effects , Animals , Benzofurans/chemistry , Benzofurans/toxicity , Benzothiazoles/chemistry , Benzothiazoles/toxicity , Binding Sites , CCAAT-Enhancer-Binding Protein-alpha/genetics , CCAAT-Enhancer-Binding Protein-alpha/metabolism , Humans , Mice , Molecular Docking Simulation , PPAR gamma/genetics , PPAR gamma/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/toxicity , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Dyrk Kinases
9.
Org Lett ; 16(23): 6240-3, 2014 Dec 05.
Article in English | MEDLINE | ID: mdl-25418801

ABSTRACT

An efficient synthetic method for versatile dibenzoxaborins based on boron-selective Suzuki-Miyaura cross-coupling between o-borylphenols and aryl halides or triflates bearing a 1,8-diaminonaphthalene-protected o-boryl group is reported. A short synthesis of defucogilvocarcin M was achieved using the proposed method in combination with several other boron-mediated transformations.


Subject(s)
Boron/chemistry , 2-Naphthylamine/analogs & derivatives , 2-Naphthylamine/chemistry , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure
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