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1.
J Med Chem ; 67(3): 2049-2065, 2024 Feb 08.
Article in English | MEDLINE | ID: mdl-38284310

ABSTRACT

Human genetic evidence shows that PDE3B is associated with metabolic and dyslipidemia phenotypes. A number of PDE3 family selective inhibitors have been approved by the FDA for various indications; however, given the undesirable proarrhythmic effects in the heart, selectivity for PDE3B inhibition over closely related family members (such as PDE3A; 48% identity) is a critical consideration for development of PDE3B therapeutics. Selectivity for PDE3B over PDE3A may be achieved in a variety of ways, including properties intrinsic to the compound or tissue-selective targeting. The high (>95%) active site homology between PDE3A and B represents a massive obstacle for obtaining selectivity at the active site; however, utilization of libraries with high molecular diversity in high throughput screens may uncover selective chemical matter. Herein, we employed a DNA-encoded library screen to identify PDE3B-selective inhibitors and identified potent and selective boronic acid compounds bound at the active site.


Subject(s)
DNA , Heart , Humans , Catalytic Domain , Cyclic Nucleotide Phosphodiesterases, Type 3
2.
J Med Chem ; 65(21): 14391-14408, 2022 11 10.
Article in English | MEDLINE | ID: mdl-36302181

ABSTRACT

E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been found in a variety of cancers and other diseases, and inhibition has been shown to decrease Myc expression. Herein, we report the identification of a series of highly potent, proline-based small-molecule p300/CBP histone acetyltransferase (HAT) inhibitors using DNA-encoded library technology in combination with high-throughput screening. The strategy of reducing ChromlogD and fluorination of metabolic soft spots was explored to improve the pharmacokinetic properties of potent p300 inhibitors. Fluorination of both cyclobutyl and proline rings of 22 led to not only reduced clearance but also improved cMyc cellular potency.


Subject(s)
CREB-Binding Protein , High-Throughput Screening Assays , Proline , Histone Acetyltransferases , Adenovirus E1A Proteins/metabolism , p300-CBP Transcription Factors , DNA , Technology
3.
J Med Chem ; 64(21): 15651-15670, 2021 11 11.
Article in English | MEDLINE | ID: mdl-34699203

ABSTRACT

A series of diarylurea inhibitors of the cardiac-specific kinase TNNI3K were developed to elucidate the biological function of TNNI3K and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular diseases. Utilizing a structure-based design, enhancements in kinase selectivity were engineered into the series, capitalizing on the established X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf. Our efforts culminated in the discovery of an in vivo tool compound 47 (GSK329), which exhibited desirable TNNI3K potency and rat pharmacokinetic properties as well as promising kinase selectivity against VEGFR2 (40-fold), p38α (80-fold), and B-Raf (>200-fold). Compound 47 demonstrated positive cardioprotective outcomes in a mouse model of ischemia/reperfusion cardiac injury, indicating that optimized exemplars from this series, such as 47, are favorable leads for discovering novel medicines for cardiac diseases.


Subject(s)
Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Urea/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Humans , Mitogen-Activated Protein Kinase 14/metabolism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins B-raf/metabolism , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemistry , Vascular Endothelial Growth Factor Receptor-2/metabolism
4.
Bioconjug Chem ; 32(2): 279-289, 2021 02 17.
Article in English | MEDLINE | ID: mdl-33523652

ABSTRACT

Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer in vivo half-lives are highly desirable. One of the most promising approaches to extend the in vivo half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of AlbuBinder 1, a small-molecule noncovalent HSA binder, to extend the in vivo half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of AlbuBinder 1 with BMP1/TLL inhibitors were prepared. In particular, conjugate c showed good solubility and a half-life extension of >20-fold versus the parent molecule in the HSA KI/KI mice, reaching half-lives of >48 h with maintained maximal inhibition of plasma BMP1/TLL. The same conjugate showed a half-life of only 3 h in the wild-type mice, suggesting that the half-life extension was principally due to specific interactions with HSA. It is envisioned that conjugation to AlbuBinder 1 should be applicable to a wide range of small molecule or peptide drugs with short half-lives. In this context, AlbuBinders represent a viable alternative to existing half-life extension technologies.


Subject(s)
Metalloproteases/metabolism , Protease Inhibitors/pharmacology , Serum Albumin, Human/metabolism , Small Molecule Libraries/metabolism , Animals , Bone Morphogenetic Protein 1/metabolism , Half-Life , Humans , Mice , Proof of Concept Study , Protease Inhibitors/pharmacokinetics
5.
Chembiochem ; 22(3): 516-522, 2021 02 02.
Article in English | MEDLINE | ID: mdl-32974990

ABSTRACT

Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As it is an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of IDO1 inhibitors with various mechanisms of inhibition is of great interest. Comparison of an apo-form-binding IDO1 inhibitor (GSK5628) to the heme-coordinating compound, epacadostat (Incyte), allows us to explore the details of the apo-binding inhibition of IDO1. Herein, we demonstrate that GSK5628 inhibits IDO1 by competing with heme for binding to a heme-free conformation of the enzyme (apo-IDO1), whereas epacadostat coordinates its binding with the iron atom of the IDO1 heme cofactor. Comparison of these two compounds in cellular systems reveals a long-lasting inhibitory effect of GSK5628, previously undescribed for other known IDO1 inhibitors. Detailed characterization of this apo-binding mechanism for IDO1 inhibition might help design superior inhibitors or could confer a unique competitive advantage over other IDO1 inhibitors vis-à-vis specificity and pharmacokinetic parameters.


Subject(s)
Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Molecular Conformation
6.
Bioorg Med Chem ; 28(23): 115791, 2020 12 01.
Article in English | MEDLINE | ID: mdl-33059303

ABSTRACT

GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.


Subject(s)
Aza Compounds/chemistry , Enzyme Inhibitors/chemistry , Quinolines/chemistry , Animals , Binding Sites , Brain/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Stability , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Humans , Intramolecular Oxidoreductases/antagonists & inhibitors , Intramolecular Oxidoreductases/metabolism , Kinetics , Male , Mice , Mice, Inbred C57BL , Molecular Dynamics Simulation , Muscle, Skeletal/chemistry , Muscle, Skeletal/metabolism , Rats , Structure-Activity Relationship
7.
ACS Med Chem Lett ; 10(11): 1518-1523, 2019 Nov 14.
Article in English | MEDLINE | ID: mdl-31749904

ABSTRACT

Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.

8.
Bioorg Med Chem ; 27(8): 1456-1478, 2019 04 15.
Article in English | MEDLINE | ID: mdl-30858025

ABSTRACT

With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50 = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50 = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50 = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Intramolecular Oxidoreductases/antagonists & inhibitors , Lipocalins/antagonists & inhibitors , Quinolines/chemistry , Quinolines/pharmacology , Animals , Drug Discovery , Enzyme Inhibitors/pharmacokinetics , Humans , Intramolecular Oxidoreductases/chemistry , Intramolecular Oxidoreductases/metabolism , Lipocalins/chemistry , Lipocalins/metabolism , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Quinolines/pharmacokinetics
9.
J Med Chem ; 61(7): 3076-3088, 2018 04 12.
Article in English | MEDLINE | ID: mdl-29561151

ABSTRACT

Structure-guided progression of a purine-derived series of TNNI3K inhibitors directed design efforts that produced a novel series of 4,6-diaminopyrimidine inhibitors, an emerging kinase binding motif. Herein, we report a detailed understanding of the intrinsic conformational preferences of the scaffold, which impart high specificity for TNNI3K. Further manipulation of the template based on the conformational analysis and additional structure-activity relationship studies provided enhancements in kinase selectivity and pharmacokinetics that furnished an advanced series of potent inhibitors. The optimized compounds (e.g., GSK854) are suitable leads for identifying new cardiac medicines and have been employed as in vivo tools in investigational studies aimed at defining the role of TNNI3K within heart failure.


Subject(s)
Cardiotonic Agents/chemical synthesis , Cardiotonic Agents/pharmacology , MAP Kinase Kinase Kinases/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Animals , Biological Availability , Cardiotonic Agents/pharmacokinetics , Computational Biology , Drug Design , ErbB Receptors/drug effects , Heart Failure/drug therapy , Humans , Models, Molecular , Molecular Conformation , Protein Serine-Threonine Kinases , Pyrimidines/pharmacokinetics , Rats , Structure-Activity Relationship
10.
J Med Chem ; 60(13): 5455-5471, 2017 07 13.
Article in English | MEDLINE | ID: mdl-28591512

ABSTRACT

The availability of high quality probes for specific protein targets is fundamental to the investigation of their function and their validation as therapeutic targets. We report the utilization of a dedicated chemoproteomic assay platform combining affinity enrichment technology with high-resolution protein mass spectrometry to the discovery of a novel nicotinamide isoster, the tetrazoloquinoxaline 41, a highly potent and selective tankyrase inhibitor. We also describe the use of 41 to investigate the biology of tankyrase, revealing the compound induced growth inhibition of a number of tumor derived cell lines, demonstrating the potential of tankyrase inhibitors in oncology.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Quinoxalines/pharmacology , Tankyrases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Ligands , Models, Molecular , Molecular Structure , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Structure-Activity Relationship , Tankyrases/metabolism
11.
Bioorg Med Chem Lett ; 26(14): 3355-3358, 2016 Jul 15.
Article in English | MEDLINE | ID: mdl-27246618

ABSTRACT

A series of selective TNNI3K inhibitors were developed by modifying the hinge-binding heterocycle of a previously reported dual TNNI3K/B-Raf inhibitor. The resulting quinazoline-containing compounds exhibit a large preference (up to 250-fold) for binding to TNNI3K versus B-Raf, are useful probes for elucidating the biological pathways associated with TNNI3K, and are leads for discovering novel cardiac medicines. GSK114 emerged as a leading inhibitor, displaying significant bias (40-fold) for TNNI3K over B-Raf, exceptional broad spectrum kinase selectivity, and adequate oral exposure to enable its use in cellular and in vivo studies.


Subject(s)
MAP Kinase Kinase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Sulfonamides/pharmacology , Dose-Response Relationship, Drug , Humans , MAP Kinase Kinase Kinases/metabolism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases , Quinazolines/chemical synthesis , Quinazolines/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry
12.
J Med Chem ; 58(18): 7431-48, 2015 Sep 24.
Article in English | MEDLINE | ID: mdl-26355916

ABSTRACT

A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9H-purin-6-yl)amino)-N-methyl-benzenesulfonamide (1) is disclosed along with fundamental structure-function relationships that delineate the role of each element of 1 for TNNI3K recognition. An X-ray structure of 1 bound to TNNI3K confirmed its Type I binding mode and is used to rationalize the structure-activity relationship and employed to design potent, selective, and orally bioavailable TNNI3K inhibitors. Identification of the 7-deazapurine heterocycle as a superior template (vs purine) and its elaboration by introduction of C4-benzenesulfonamide and C7- and C8-7-deazapurine substituents produced compounds with substantial improvements in potency (>1000-fold), general kinase selectivity (10-fold improvement), and pharmacokinetic properties (>10-fold increase in poDNAUC). Optimal members of the series have properties suitable for use in in vitro and in vivo experiments aimed at elucidating the role of TNNI3K in cardiac biology and serve as leads for developing novel heart failure medicines.


Subject(s)
MAP Kinase Kinase Kinases/antagonists & inhibitors , Purines/chemistry , Administration, Oral , Animals , Cell Line , Crystallography, X-Ray , Humans , Male , Protein Binding , Protein Conformation , Protein Serine-Threonine Kinases , Purines/pharmacokinetics , Purines/pharmacology , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology
13.
J Med Chem ; 58(17): 7021-56, 2015 Sep 10.
Article in English | MEDLINE | ID: mdl-26267483

ABSTRACT

Starting from the micromolar 8-quinoline carboxamide high-throughput screening hit 1a, a systematic exploration of the structure-activity relationships (SAR) of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the identification of approximately 10-100-fold more potent human CD38 inhibitors. Several of these molecules also exhibited pharmacokinetic parameters suitable for in vivo animal studies, including low clearances and decent oral bioavailability. Two of these CD38 inhibitors, 1ah and 1ai, were shown to elevate NAD tissue levels in liver and muscle in a diet-induced obese (DIO) C57BL/6 mouse model. These inhibitor tool compounds will enable further biological studies of the CD38 enzyme as well as the investigation of the therapeutic implications of NAD enhancement in disease models of abnormally low NAD.


Subject(s)
ADP-ribosyl Cyclase 1/antagonists & inhibitors , Amides/chemistry , Aminoquinolines/chemistry , NAD/metabolism , Quinolines/chemistry , Amides/chemical synthesis , Amides/pharmacology , Aminoquinolines/chemical synthesis , Aminoquinolines/pharmacology , Animals , Biological Availability , Crystallography, X-Ray , Humans , Hydrolysis , Liver/metabolism , Membranes, Artificial , Mice, Inbred C57BL , Models, Molecular , Muscle, Skeletal/metabolism , Obesity/metabolism , Permeability , Protein Conformation , Quinolines/chemical synthesis , Quinolines/pharmacology , Stereoisomerism , Structure-Activity Relationship
14.
Arch Biochem Biophys ; 564: 156-63, 2014 Dec 15.
Article in English | MEDLINE | ID: mdl-25250980

ABSTRACT

hCD157 catalyzes the hydrolysis of nicotinamide riboside (NR) and nicotinic acid riboside (NAR). The release of nicotinamide or nicotinic acid from NR or NAR was confirmed by spectrophotometric, HPLC and NMR analyses. hCD157 is inactivated by a mechanism-based inhibitor, 2'-deoxy-2'-fluoro-nicotinamide arabinoside (fNR). Modification of the enzyme during the catalytic cycle by NR, NAR, or fNR increased the intrinsic protein fluorescence by approximately 50%. Pre-steady state and steady state data were used to derive a minimal kinetic scheme for the hydrolysis of NR. After initial complex formation a reversible step (360 and 30s(-1)) is followed by a slow irreversible step (0.1s(-1)) that defined the rate limiting step, or kcat. The calculated KMapp value for NR in the hydrolytic reaction is 6nM. The values of the kinetic constants suggest that one biological function of cell-surface hCD157 is to bind and slowly hydrolyze NR, possibly converting it to a ligand-activated receptor. Differences in substrate preference between hCD157 and hCD38 were rationalized through a comparison of the crystal structures of the two proteins. This comparison identified several residues in hCD157 (F108 and F173) that can potentially hinder the binding of dinucleotide substrates (NAD+).


Subject(s)
ADP-ribosyl Cyclase/chemistry , Antigens, CD/chemistry , Niacinamide/analogs & derivatives , Ribonucleosides/chemistry , ADP-ribosyl Cyclase/genetics , ADP-ribosyl Cyclase/metabolism , Animals , Antigens, CD/genetics , Antigens, CD/metabolism , CHO Cells , Catalysis , Cricetinae , Cricetulus , GPI-Linked Proteins/chemistry , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Humans , Hydrolysis , Kinetics , Niacinamide/chemistry , Niacinamide/genetics , Niacinamide/metabolism , Nuclear Magnetic Resonance, Biomolecular , Pyridinium Compounds , Ribonucleosides/genetics , Ribonucleosides/metabolism
15.
Bioorg Med Chem Lett ; 23(12): 3584-8, 2013 Jun 15.
Article in English | MEDLINE | ID: mdl-23664879

ABSTRACT

1-(1,3,5-Triazin-yl)piperidine-4-carboxamide inhibitors of soluble epoxide hydrolase were identified from high through-put screening using encoded library technology. The triazine heterocycle proved to be a critical functional group, essential for high potency and P450 selectivity. Phenyl group substitution was important for reducing clearance, and establishing good oral exposure. Based on this lead optimization work, 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[[4-bromo-2-(trifluoromethoxy)]-phenyl]methyl}-4-piperidinecarboxamide (27) was identified as a useful tool compound for in vivo investigation. Robust effects on a serum biomarker, 9, 10-epoxyoctadec-12(Z)-enoic acid (the epoxide derived from linoleic acid) were observed, which provided evidence of robust in vivo target engagement and the suitability of 27 as a tool compound for study in various disease models.


Subject(s)
Amides/chemistry , Amides/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Epoxide Hydrolases/antagonists & inhibitors , Piperidines/chemistry , Piperidines/pharmacology , Amides/chemical synthesis , Drug Discovery , Enzyme Inhibitors/chemical synthesis , Epoxide Hydrolases/metabolism , Humans , Models, Molecular , Piperidines/chemical synthesis , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/chemistry , Triazines/pharmacology
16.
PLoS One ; 7(8): e43019, 2012.
Article in English | MEDLINE | ID: mdl-22952628

ABSTRACT

Proline-specific dipeptidyl peptidases (DPPs) are emerging targets for drug development. DPP4 inhibitors are approved in many countries, and other dipeptidyl peptidases are often referred to as DPP4 activity- and/or structure-homologues (DASH). Members of the DASH family have overlapping substrate specificities, and, even though they share low sequence identity, therapeutic or clinical cross-reactivity is a concern. Here, we report the structure of human DPP7 and its complex with a selective inhibitor Dab-Pip (L-2,4-diaminobutyryl-piperidinamide) and compare it with that of DPP4. Both enzymes share a common catalytic domain (α/ß-hydrolase). The catalytic pocket is located in the interior of DPP7, deep inside the cleft between the two domains. Substrates might access the active site via a narrow tunnel. The DPP7 catalytic triad is completely conserved and comprises Ser162, Asp418 and His443 (corresponding to Ser630, Asp708 and His740 in DPP4), while other residues lining the catalytic pockets differ considerably. The "specificity domains" are structurally also completely different exhibiting a ß-propeller fold in DPP4 compared to a rare, completely helical fold in DPP7. Comparing the structures of DPP7 and DPP4 allows the design of specific inhibitors and thus the development of less cross-reactive drugs. Furthermore, the reported DPP7 structures shed some light onto the evolutionary relationship of prolyl-specific peptidases through the analysis of the architectural organization of their domains.


Subject(s)
Dipeptidyl Peptidase 4/genetics , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/chemistry , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism , Proline/chemistry , Amino Acids/chemistry , Animals , Base Sequence , CHO Cells , Catalysis , Catalytic Domain , Cricetinae , Dimerization , Dipeptidyl Peptidase 4/chemistry , Evolution, Molecular , Humans , Insecta , Molecular Sequence Data , Protein Binding , Protein Structure, Tertiary , Substrate Specificity
17.
J Med Chem ; 55(16): 7193-207, 2012 Aug 23.
Article in English | MEDLINE | ID: mdl-22827572

ABSTRACT

Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.


Subject(s)
Adenine/analogs & derivatives , Antineoplastic Agents/chemical synthesis , Indoles/chemical synthesis , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , eIF-2 Kinase/antagonists & inhibitors , Adenine/chemical synthesis , Adenine/chemistry , Adenine/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Availability , Cell Line, Tumor , Crystallography, X-Ray , Dogs , Drug Screening Assays, Antitumor , Female , Humans , Indoles/chemistry , Indoles/pharmacology , Male , Mice , Mice, Nude , Models, Molecular , Neoplasm Transplantation , Phosphorylation , Protein Conformation , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Transplantation, Heterologous
18.
Biochem Pharmacol ; 78(12): 1438-47, 2009 Dec 15.
Article in English | MEDLINE | ID: mdl-19665448

ABSTRACT

Insulin-like growth factor 1 receptor (IGF-1R) is an attractive target for anti-cancer therapy due to its anti-apoptotic effect on tumor cells, but inhibition of insulin receptor (IR) may have undesired metabolic consequences. The primary sequences of the ATP substrate-binding sites of these receptors are identical and the crystal structures of the activated kinase domains are correspondingly similar. Thus, most small-molecule inhibitors described to date are equally potent against the activated kinase domains of IGF-1R and IR. In contrast, the non-phosphorylated kinase domains of these receptors have several structural features that may accommodate differences in binding affinity for kinase inhibitors. We used a cell-based assay measuring IGF-1R autophosphorylation as an inhibitor screen, and identified a potent purine derivative that is selective compared to IR. Surprisingly, the compound is a weak inhibitor of the activated IGF-1R tyrosine kinase domain. Biochemical and structural studies are presented that indicate the compound preferentially binds to the ATP site of non-phosphorylated IGF-1R compared to phosphorylated IGF-1R. The potential selectivity and potency advantages of this binding mode are discussed.


Subject(s)
Receptor, IGF Type 1/antagonists & inhibitors , Receptor, Insulin/drug effects , Adipocytes/drug effects , Animals , Binding Sites , Humans , Inhibitory Concentration 50 , Mice , NIH 3T3 Cells , Phosphorylation , Phosphotransferases/antagonists & inhibitors , Signal Transduction/drug effects , Structure-Activity Relationship
20.
Bioorg Med Chem Lett ; 19(3): 817-20, 2009 Feb 01.
Article in English | MEDLINE | ID: mdl-19111461

ABSTRACT

Two new series of potent and selective dual EGFR/ErbB-2 kinase inhibitors derived from novel thienopyrimidine cores have been identified. Isomeric thienopyrimidine cores were evaluated as isosteres for a 4-anilinoquinazoline core and several analogs containing the thieno[3,2-d]pyrimidine core showed anti-proliferative activity with IC(50) values less than 1 microM against human tumor cells in vitro.


Subject(s)
Antineoplastic Agents/pharmacology , Chemistry, Pharmaceutical/methods , ErbB Receptors/chemistry , Pyrimidines/chemistry , Receptor, ErbB-2/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Proliferation , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Lapatinib , Models, Chemical , Molecular Conformation , Quinazolines/pharmacology
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