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1.
J Med Chem ; 62(3): 1167-1179, 2019 02 14.
Article in English | MEDLINE | ID: mdl-30652849

ABSTRACT

Retinoic acid receptor-related orphan receptor γt (RORγt) agonists are expected to provide a novel class of immune-activating anticancer drugs via activation of Th17 cells and Tc17 cells. Herein, we describe a novel structure-based functionality switching approach from in house well-optimized RORγt inverse agonists to potent RORγt agonists. We succeeded in the identification of potent RORγt agonist 5 without major chemical structure change. The biochemical response was validated by molecular dynamics simulation studies that showed a helix 12 stabilization effect of RORγt agonists. These results indicate that targeting helix 12 is an attractive and novel medicinal chemistry strategy for switching existing RORγt inverse agonists to agonists.


Subject(s)
Drug Design , Drug Inverse Agonism , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Animals , High-Throughput Screening Assays , Molecular Dynamics Simulation , Structure-Activity Relationship , Th17 Cells/drug effects
2.
Inflamm Bowel Dis ; 24(6): 1251-1265, 2018 05 18.
Article in English | MEDLINE | ID: mdl-29669006

ABSTRACT

Background: Anti-tumor necrosis factor alpha (anti-TNFα) therapy has become the mainstay of therapy for Crohn's disease (CD). However, post-therapy, the recurrence rate is still high. The aim of this study was to dissect the molecular mechanism for recurrence of CD treated with anti-TNFα therapy and investigate novel therapeutic options that could induce complete remission. Methods: We re-analyzed publicly available mucosal gene expression data from CD patients pre- and post-infliximab therapy to extract the transcriptional differences between responders and healthy controls. We used a systematic computational approach based on identified differences to discover novel therapies and validated this prediction through in vitro and in vivo experimentation. Results: We identified a set of 3545 anti-TNFα therapy-untreatable genes (TUGs) that are significantly regulated in intestinal epithelial cells, which remain altered during remission. Pathway enrichment analysis of these genes clearly showed excessive growth state and suppressed terminal differentiation, whereas immune components were clearly resolved. Through in silico screening strategy, we observed that MEK inhibitors were predicted to revert expression of genes dysregulated in infliximab responders. In vitro transcriptome analysis demonstrated that selective MEK1/2 inhibitor significantly normalized reference genes from TUGs. In addition, in vitro functional study proved that MEK1/2 inhibitor facilitated intestinal epithelial differentiation. Finally, using murine colitis model, administration of MEK1/2 inhibitor significantly improved diarrhea and histological score. Conclusions: Our data revealed the abnormalities in anti-TNFα responders' CD colons that would be cause of recurrence of CD. Also, we provided evidence regarding MEK1/2 inhibitor as a potential treatment against CD to achieve sustainable remission.


Subject(s)
Crohn Disease/drug therapy , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Caco-2 Cells , Colon/pathology , Crohn Disease/metabolism , Disease Models, Animal , Female , Gene Expression Regulation/drug effects , Humans , Infliximab , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Recurrence , Remission Induction
3.
ChemMedChem ; 11(24): 2682-2689, 2016 12 16.
Article in English | MEDLINE | ID: mdl-27863031

ABSTRACT

Indoleamine 2,3-dioxygenase 1 (IDO1) has emerged as a key target for cancer therapy, as IDO1 plays a critical role in the capacity of tumor cells to evade the immune system. The pyrrolopiperazinone alkaloid longamide B and its derivatives were identified as novel IDO1 inhibitors based on docking studies and small library synthesis. The thioamide derivative showed higher IDO1 inhibitory activity than longamide B, and displayed an activity similar to that of a representative IDO1 inhibitor, 1-methyl-tryptophan. These results suggest that the pyrrolopiperazinone scaffold of longamide B could be used in the development of IDO1 inhibitors.


Subject(s)
Drug Discovery , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Pyrroles/chemistry , Pyrroles/pharmacology , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Matrix Attachment Regions , Models, Molecular , Piperazines/chemistry , Piperazines/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology
4.
Bioorg Med Chem ; 23(15): 4777-4791, 2015 Aug 01.
Article in English | MEDLINE | ID: mdl-26094943

ABSTRACT

As we previously reported, N-methylpyrrolo[3,2-c]pyridine derivatives 1 (TAK-441) was discovered as a clinical candidate of hedgehog (Hh) signaling inhibitor by modification of the upper part. We next focused on modification of the lower part including core skeletons to discover new Hh signaling inhibitors with novel core rings. Efforts to find novel chemotypes by using X-ray single crystal structure analysis led to some potent Hh signaling inhibitors (2c, 2d, 2e, 2f) with novel core ring systems, which had benzamide moiety at the 5-position as a key component for potent activity. The suppression of Gli1 expression with these new Hh signaling inhibitors were weaker than that of compound 1 (TAK-441) because of low pharmacokinetic property. We recognized again TAK-441 is a good compound as clinical candidate with good structural and pharmacokinetic advantages.


Subject(s)
Hedgehog Proteins/antagonists & inhibitors , Pyridines/chemistry , Signal Transduction , Animals , Crystallography, X-Ray , Drug Evaluation, Preclinical , Genes, Reporter , Half-Life , Hedgehog Proteins/metabolism , Humans , Mice , Molecular Conformation , Pyridines/chemical synthesis , Pyridines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Signal Transduction/drug effects , Structure-Activity Relationship
5.
Bioorg Med Chem ; 21(24): 7938-54, 2013 Dec 15.
Article in English | MEDLINE | ID: mdl-24169315

ABSTRACT

We previously reported octahydropyrrolo[1,2-a]pyrazine derivative 2 (T-3256336) as a potent antagonist for inhibitors of apoptosis (IAP) proteins. Because compound 2 was susceptible to MDR1 mediated efflux, we developed another scaffold, hexahydropyrazino[1,2-a]indole, using structure-based drug design. The fused benzene ring of this scaffold was aimed at increasing the lipophilicity and decreasing the basicity of the scaffold to improve the membrane permeability across MDR1 expressing cells. We established a chiral pool synthetic route to yield the desired tricyclic chiral isomers. Chemical modification of the core scaffold led to a representative compound 50, which showed strong inhibition of IAP binding (X chromosome-linked IAP [XIAP]: IC50 23 nM and cellular IAP [cIAP]: IC50 1.1 nM) and cell growth inhibition (MDA-MB-231 cells: GI50 2.8 nM) with high permeability and low potential of MDR1 substrate.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Membrane Permeability/drug effects , Drug Design , Indoles/pharmacology , Inhibitor of Apoptosis Proteins/pharmacology , Pyrazines/pharmacology , ATP Binding Cassette Transporter, Subfamily B , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Indoles/chemical synthesis , Indoles/chemistry , Inhibitor of Apoptosis Proteins/chemical synthesis , Inhibitor of Apoptosis Proteins/chemistry , Models, Molecular , Molecular Structure , Pyrazines/chemical synthesis , Pyrazines/chemistry , Structure-Activity Relationship
6.
Bioorg Med Chem ; 21(18): 5725-37, 2013 Sep 15.
Article in English | MEDLINE | ID: mdl-23928071

ABSTRACT

We recently reported the discovery of octahydropyrrolo[1,2-a]pyrazine A as a lead compound for an inhibitor of apoptosis proteins (IAP) antagonist. To develop IAP antagonists with favorable PK profiles, we designed novel tri-cyclic compounds, octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazines 1 and 2 based on co-crystal structural analysis of A with cellular IAP-1 (cIAP-1). The additional cyclopropane moiety was used to block the predicted metabolic site of compound A without detriment to the binding affinity for cIAP. Compounds 1 and 2 were stereoselectively synthesized via intermediates 4a and 5b', which were obtained by Simmons-Smith cyclopropanation of ethylester 3a and silyl ether 3b'. Compounds 1 and 2 showed strong growth inhibition in MDA-MB-231 breast cancer cells and improved metabolic stability in comparison to A. Compound 2 exhibited significant in vivo PD effects to increase tumor necrosis factor-alpha mRNA in a dose dependent manner.


Subject(s)
Drug Design , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Pyrazines/chemistry , Pyrroles/chemical synthesis , Animals , Benzopyrans/chemical synthesis , Benzopyrans/pharmacokinetics , Benzopyrans/therapeutic use , Binding Sites , Breast Neoplasms/drug therapy , Cell Line, Tumor , Crystallography, X-Ray , Female , Half-Life , Humans , Inhibitor of Apoptosis Proteins/metabolism , Mice , Molecular Dynamics Simulation , Protein Structure, Tertiary , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Pyrazines/therapeutic use , Pyrroles/chemistry , Pyrroles/pharmacokinetics , Pyrroles/therapeutic use , RNA, Messenger/metabolism , Stereoisomerism , Transplantation, Heterologous , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
7.
J Med Chem ; 56(3): 1228-46, 2013 Feb 14.
Article in English | MEDLINE | ID: mdl-23298277

ABSTRACT

To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC(50): 1.3 nM) and XIAP (IC(50): 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI(50): 1.8 nM) in MDA-MB-231 breast cancer cells. X-ray crystallographic analysis of compound 45 bound to XIAP and to cIAP1 was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound 45 over XIAP. Because of its potent IAP inhibitory activities, compound 45 (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: -53% at 30 mg/kg).


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Oligopeptides/chemistry , Oligopeptides/pharmacology , Peptidomimetics , Proline/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Crystallography, X-Ray , Drug Design , Magnetic Resonance Spectroscopy , Models, Molecular , Oligopeptides/chemical synthesis
8.
Bioorg Med Chem ; 20(18): 5507-17, 2012 Sep 15.
Article in English | MEDLINE | ID: mdl-22898254

ABSTRACT

We recently reported the discovery of the novel pyrrolo[3,2-c]quinoline-4-one derivative 1 as a potent inhibitor of Hedgehog (Hh) pathway signaling. However, the PK evaluation of 1 at high dosage (100 mg/kg) revealed the C(max) value 3.63 µg/mL, likely due to poor solubility of this compound. Efforts to improve solubility by reducing the aromatic ring count of the core system led to N-methylpyrrolo[3,2-c]pyridine derivative 11. Further optimization of the 3-alkoxy group led to compound 11d with acceptable solubility and potent Hh inhibitory activity. Compound 11d suppressed transcription factor Gli1 mRNA expression in tumor-associated stromal tissue and inhibited tumor growth (treatment/control ratio, 3%) in a mouse medulloblastoma allograft model owing to the improved PK profile based on increased solubility. Compound 11d (TAK-441) is currently in clinical trials for the treatment of advanced solid tumors.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Hedgehog Proteins/antagonists & inhibitors , Medulloblastoma/drug therapy , Pyridines/pharmacology , Pyrroles/pharmacology , Signal Transduction/drug effects , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Hedgehog Proteins/metabolism , Humans , Kruppel-Like Transcription Factors/antagonists & inhibitors , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Mice , Mice, Nude , Models, Molecular , Molecular Structure , NIH 3T3 Cells , Pyridines/administration & dosage , Pyridines/chemical synthesis , Pyridines/chemistry , Pyrroles/administration & dosage , Pyrroles/chemical synthesis , Pyrroles/chemistry , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/genetics , Solubility , Structure-Activity Relationship , Transplantation, Homologous , Zinc Finger Protein GLI1
9.
Bioorg Med Chem ; 20(18): 5496-506, 2012 Sep 15.
Article in English | MEDLINE | ID: mdl-22910224

ABSTRACT

The Hedgehog (Hh) signaling pathway plays a significant role in the regulation of cell growth and differentiation during embryonic development. Since activation of the Hh signaling pathway is implicated in several types of human cancers, inhibitors of this pathway could be promising anticancer agents. Using high throughput screening, thieno[3,2-c]quinoline-4-one derivative 9a was identified as a compound of interest with potent in vitro activity but poor metabolic stability. Our efforts focused on enhancement of in vitro inhibitory activity and metabolic stability, including core ring conversion and side chain optimization. This led to the discovery of pyrrolo[3,2-c]quinoline-4-one derivative 12b, which has a structure distinct from previously reported Hh signaling inhibitors. Compound 12b suppressed stromal Gli1 mRNA expression in a murine model and demonstrated antitumor activity in a murine medulloblastoma allograft model.


Subject(s)
4-Quinolones/pharmacology , Antineoplastic Agents/pharmacology , Drug Discovery , Hedgehog Proteins/antagonists & inhibitors , Medulloblastoma/drug therapy , Signal Transduction/drug effects , 4-Quinolones/chemical synthesis , 4-Quinolones/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Hedgehog Proteins/metabolism , High-Throughput Screening Assays , Humans , Kruppel-Like Transcription Factors/antagonists & inhibitors , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Mice , Mice, Knockout , Models, Molecular , Molecular Structure , NIH 3T3 Cells , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/genetics , Structure-Activity Relationship , Transplantation, Homologous , Zinc Finger Protein GLI1
10.
Glycoconj J ; 27(1): 69-77, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19757026

ABSTRACT

Using recombinant tetanus toxin H(C) fragment (rTT-H(C)) as carrier, we prepared multimeric bivalent immunogens featuring the synthetic hexasaccharide fragment of O-PS of Vibrio cholerae O:1, serotype Ogawa, in combination with either the synthetic hexasaccharide fragment of O-PS of Vibrio cholerae O:1, serotype Inaba, or a synthetic disaccharide tetrapeptide peptidoglycan fragment as adjuvant. The conjugation reaction was effected by squaric acid chemistry and monitored in virtually real time by SELDI-TOF MS. In this way, we could prepare well-defined immunogens with predictable carbohydrate-carrier ratio, whose molecular mass and the amount of each saccharide attached could be independently determined. The ability to prepare such neoglycoconjugates opens unprecedented possibilities for preparation of conjugate vaccines for bacterial diseases from synthetic carbohydrates.


Subject(s)
Adjuvants, Immunologic/chemical synthesis , Glycopeptides/immunology , Oligosaccharides/immunology , Peptide Fragments/immunology , Tetanus Toxin/immunology , Vaccines, Synthetic/immunology , Carbohydrate Conformation , Carbohydrate Sequence , Glycoconjugates/chemical synthesis , Glycoconjugates/chemistry , Glycopeptides/chemistry , Molecular Sequence Data , Oligosaccharides/chemistry , Peptide Fragments/chemistry , Recombinant Proteins/chemistry , Tetanus Toxin/chemistry
11.
J Endotoxin Res ; 13(3): 189-96, 2007.
Article in English | MEDLINE | ID: mdl-17621561

ABSTRACT

Partial structures of peptidoglycan were chemically synthesized for elucidation of their precise biological activities. By using an efficient synthetic strategy, mono-, di-, tetra- and octasaccharide fragments of peptidoglycan were synthesized in good yields. The biological activity of synthetic fragments of peptidoglycan was evaluated by induction of TNF-alpha from human monocytes, and TLR2 and NOD2 dependencies by using transfected HEK293 cells, respectively. We revealed that TLR2 was not stimulated by the series of synthetic peptidoglycan partial structures, whereas NOD2 recognizes the partial structures containing the MDP moiety. We also synthesized potent NOD1 agonists, which showed several hundred-fold stronger activity than gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP). Interaction of PGRPs with synthetic peptidoglycan fragments is also described.


Subject(s)
Peptide Fragments/chemical synthesis , Peptide Fragments/pharmacology , Peptidoglycan/chemistry , Peptidoglycan/immunology , Cell Line , Humans , Molecular Structure , Monocytes/chemistry , Nod1 Signaling Adaptor Protein/metabolism , Nod2 Signaling Adaptor Protein/agonists , Nod2 Signaling Adaptor Protein/metabolism , Peptide Fragments/immunology , Peptidoglycan/pharmacology , Toll-Like Receptor 2/genetics , Toll-Like Receptor 4/genetics , Transfection , Tumor Necrosis Factor-alpha/metabolism
12.
Org Biomol Chem ; 4(2): 232-42, 2006 Jan 21.
Article in English | MEDLINE | ID: mdl-16391765

ABSTRACT

The peptidoglycan (PG) bacterial cell wall glycoconjugate has been well known as a strong immunopotentiator. Partial structures of PG were chemically synthesized for elucidation of precise biological activities. Effective construction of distinct repeating glycans of PG was accomplished by the coupling of a key disaccharide glucosaminyl-beta(1-4)-muramic acid unit. Stereoselective glycosylation of disaccharide units was achieved by neighboring group participation of the N-Troc (Troc = 2,2,2-trichloroethoxycarbonyl) group and appropriate reactivity of N-Troc-glucosaminyl trichloroacetimidate. By using an efficient synthetic strategy, mono-, di-, tetra- and octasaccharide fragments of PG were synthesized in high yields. The biological activity of synthetic fragments of PG was evaluated by induction of tumor necrosis factor-alpha (TNF-alpha) from human monocytes, and toll-like receptor 2 (TLR2) and Nod2 dependencies by using transfected HEK293 cells, respectively. Here we reveal that TLR2 was not stimulated by the series of synthetic PG partial structures, whereas Nod2 recognizes the partial structures containing the MDP moiety.


Subject(s)
Peptide Fragments/chemical synthesis , Peptide Fragments/pharmacology , Peptidoglycan/chemistry , Peptidoglycan/immunology , Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Acetylmuramyl-Alanyl-Isoglutamine/chemistry , Cell Line , Cell Wall/chemistry , Humans , Monocytes , Nod2 Signaling Adaptor Protein/drug effects , Oligosaccharides/chemical synthesis , Peptide Fragments/immunology , Peptidoglycan/pharmacology , Toll-Like Receptor 2/drug effects , Tumor Necrosis Factor-alpha/drug effects
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