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1.
Eur J Med Chem ; 275: 116598, 2024 Sep 05.
Article in English | MEDLINE | ID: mdl-38925013

ABSTRACT

Lactate dehydrogenase-A (LDHA) is the major isoform of lactate dehydrogenases (LDH) that is overexpressed and linked to poor survival in pancreatic ductal adenocarcinoma (PDAC). Despite some progress, current LDH inhibitors have poor structural and physicochemical properties or exhibit unfavorable pharmacokinetics that have hampered their development. The present study reports the synthesis and biological evaluation of a novel class of LDHA inhibitors comprising a succinic acid monoamide motif. Compounds 6 and 21 are structurally related analogs that demonstrated potent inhibition of LDHA with IC50s of 46 nM and 72 nM, respectively. We solved cocrystal structures of compound 21-bound to LDHA that showed that the compound binds to a distinct allosteric site between the two subunits of the LDHA tetramer. Inhibition of LDHA correlated with reduced lactate production and reduction of glycolysis in MIA PaCa-2 pancreatic cancer cells. The lead compounds inhibit the proliferation of human pancreatic cancer cell lines and patient-derived 3D organoids and exhibit a synergistic cytotoxic effect with the OXPHOS inhibitor phenformin. Unlike current LDHA inhibitors, 6 and 21 have appropriate pharmacokinetics and ligand efficiency metrics, exhibit up to 73% oral bioavailability, and a cumulative half-life greater than 4 h in mice.


Subject(s)
Antineoplastic Agents , Cell Proliferation , Enzyme Inhibitors , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Animals , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Cell Proliferation/drug effects , Administration, Oral , Mice , Structure-Activity Relationship , Molecular Structure , Drug Screening Assays, Antitumor , Biological Availability , Dose-Response Relationship, Drug , L-Lactate Dehydrogenase/antagonists & inhibitors , L-Lactate Dehydrogenase/metabolism , Cell Line, Tumor , Models, Molecular
2.
Molecules ; 28(4)2023 Feb 17.
Article in English | MEDLINE | ID: mdl-36838932

ABSTRACT

New sets of ibuprofen and indomethacin conjugates comprising triazolyl heterocycle were synthesized via click chemistry, adopting an optimized protocol through the molecular hybridization approach affording the targeted agents in good yields. The new non-steroidal anti-inflammatory drug (NSAID) conjugates were designed and synthesized and could be considered as potential drug candidates for the treatment of pain and inflammation. The anti-inflammatory properties were investigated for all the synthesized conjugates. Among 14 synthesized conjugates, four (5a, 5b, 5d, and 5e) were found to have significant anti-inflammatory properties potency 117.6%, 116.5%, 93.8%, and 109.1% in comparison to reference drugs ibuprofen (97.2%) and indomethacin (100%) in the rat paw edema carrageenan test without any ulcerogenic liability. The suppression effect of cytokines IL-6, TNF-α, and iNOS in addition to NO in the LPS-induced RAW264.7 cells supports the promising anti-inflammatory properties observed in the ibuprofen conjugates. In addition, several conjugates showed promising peripheral and central analgesic activity. The selectivity index (SI) of compound 5a (23.096) indicates the significant efficacy and selectivity for COX-2 over COX-1. Molecular modeling (docking and QSAR) studies described the observed biological properties.


Subject(s)
Cyclooxygenase 2 Inhibitors , Ibuprofen , Rats , Animals , Cyclooxygenase 2 Inhibitors/pharmacology , Ibuprofen/therapeutic use , Structure-Activity Relationship , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents/pharmacology , Indomethacin/pharmacology , Carrageenan/adverse effects , Cyclooxygenase 2/metabolism , Edema/drug therapy , Molecular Docking Simulation
3.
J Chem Inf Model ; 63(3): 1028-1043, 2023 02 13.
Article in English | MEDLINE | ID: mdl-36646658

ABSTRACT

It is imperative to explore the gigantic available chemical space to identify new scaffolds for drug lead discovery. Identifying potent hits from virtual screening of large chemical databases is challenging and computationally demanding. Rather than the traditional two-dimensional (2D)/three-dimensional (3D) approaches on smaller chemical libraries of a few hundred thousand compounds, we screened a ZINC library of 15 million compounds using multiple computational methods. Here, we present the successful application of a virtual screening methodology that identifies several chemotypes as starting hits against lactate dehydrogenase-A (LDHA). From 29 compounds identified from virtual screening, 17 (58%) showed IC50 values < 63 µM, two showed single-digit micromolar inhibition, and the most potent hit compound had IC50 down to 117 nM. We enriched the database and employed an ensemble approach by combining 2D fingerprint similarity searches, pharmacophore modeling, molecular docking, and molecular dynamics. WaterMap calculations were carried out to explore the thermodynamics of surface water molecules and gain insights into the LDHA binding pocket. The present work has led to the discovery of two new chemical classes, including compounds with a succinic acid monoamide moiety or a hydroxy pyrimidinone ring system. Selected hits block lactate production in cells and inhibit pancreatic cancer cell lines with cytotoxicity IC50 down to 12.26 µM against MIAPaCa-2 cells and 14.64 µM against PANC-1, which, under normoxic conditions, is already comparable or more potent than most currently available known LDHA inhibitors.


Subject(s)
Molecular Dynamics Simulation , Pancreatic Neoplasms , Humans , Molecular Docking Simulation , Lactate Dehydrogenase 5 , Small Molecule Libraries/pharmacology , Small Molecule Libraries/chemistry , Pancreatic Neoplasms/drug therapy
4.
Bioorg Med Chem ; 78: 117131, 2023 01 15.
Article in English | MEDLINE | ID: mdl-36571976

ABSTRACT

To follow up on our previous report on bivalent compounds exhibiting potent co-operative binding at dopamine D2 receptors, we modified the structure of the linker in our earlier bivalent molecules (S)-6-((9-(((R)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)nonyl)-(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol (Ia) and (S)-6-((10-(((R)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)decyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol (Ib) (Fig. 1) connecting the two pharmaophoric moieties to observe any tolerance in maintaining similar affinities and potencies. Specifically, we introduced aromatic and piperazine moieties in the linker to explore their effect. Overall, similar activities at D2 receptors as observed in our earlier study was maintained in the new molecules e.g. (6S,6'S)-6,6'-((1,4-phenylenebis(ethane-2,1-diyl))bis(propylazanediyl))bis(5,6,7,8-tetrahydronaphthalen-1-ol) (D-382) (Ki, D2 = 3.88 nM). The aromatic moiety in D-382 was next functionalized by introducing hydroxyl groups to mimic polyhydroxy natural products which are known to interact with amyloidogenic proteins. Such a transformation resulted in development of compounds like 2,5-bis(2-(((S)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)benzene-1,4-diol (D-666) (Ki, D2 = 7.62 nM) which retained similar affinity and potency at D2 receptors. Such dihydroxyl compounds turned out to be potent inhibitors against aggregation and toxicity of recombinant alpha synuclein protein. The work reported here is in line with our overall goal to develop multifunctional dopamine agonist for symptomatic and disease modifying treatment of Parkinson's disease.


Subject(s)
Dopamine Agonists , Receptors, Dopamine D2 , alpha-Synuclein , Dopamine Agonists/pharmacology , Dopamine Agonists/chemistry , Piperazines/pharmacology , Receptors, Dopamine D1 , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/agonists
5.
J Biol Chem ; 298(7): 102069, 2022 07.
Article in English | MEDLINE | ID: mdl-35623388

ABSTRACT

Major depressive disorder is a critical public health problem with a lifetime prevalence of nearly 17% in the United States. One potential therapeutic target is the interaction between hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and an auxiliary subunit of the channel named tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). HCN channels regulate neuronal excitability in the mammalian hippocampus, and recent work has established that antagonizing HCN function rescues cognitive impairment caused by chronic stress. Here, we utilize a high-throughput virtual screen to find small molecules capable of disrupting the TRIP8b-HCN interaction. We found that the hit compound NUCC-0200590 disrupts the TRIP8b-HCN interaction in vitro and in vivo. These results provide a compelling strategy for developing new small molecules capable of disrupting the TRIP8b-HCN interaction.


Subject(s)
Depressive Disorder, Major , Animals , Cyclic Nucleotide-Gated Cation Channels/metabolism , Depressive Disorder, Major/metabolism , Hippocampus/metabolism , Humans , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism , Mammals/metabolism , Neurons/metabolism
6.
Int J Mol Sci ; 21(17)2020 Aug 30.
Article in English | MEDLINE | ID: mdl-32872646

ABSTRACT

The usage of nanomaterials for cancer treatment has been a popular research focus over the past decade. Nanomaterials, including polymeric nanomaterials, metal nanoparticles, semiconductor quantum dots, and carbon-based nanomaterials such as graphene oxide (GO), have been used for cancer cell imaging, chemotherapeutic drug targeting, chemotherapy, photothermal therapy, and photodynamic therapy. In this review, we discuss the concept of targeted nanoparticles in cancer therapy and summarize the in vivo biocompatibility of graphene-based nanomaterials. Specifically, we discuss in detail the chemistry and properties of GO and provide a comprehensive review of functionalized GO and GO-metal nanoparticle composites in nanomedicine involving anticancer drug delivery and cancer treatment.


Subject(s)
Antineoplastic Agents/therapeutic use , Drug Delivery Systems , Graphite/chemistry , Metal Nanoparticles/chemistry , Nanomedicine , Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Humans
8.
Curr Top Med Chem ; 18(6): 505-524, 2018.
Article in English | MEDLINE | ID: mdl-29773061

ABSTRACT

Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (αKG). IDH1 and IDH2 regulate several cellular processes, including oxidative respiration, glutamine metabolism, lipogenesis, and cellular defense against oxidative damage. Mutations in IDH1 and IDH2 have recently been observed in multiple tumors, including gliomas, acute myeloid leukemia, myelodysplastic syndromes, and chondrosarcoma. IDH1 and IDH2 mutations involve a gain in neomorphic activity that catalyzes αKG conversion to (R)-2- hydroxyglutarate ((R)-2HG). IDH mutation-mediated accumulation of (R)-2HG results in epigenetic dysregulation, altered gene expression, and a block in cellular differentiation. Targeting mutant IDH by development of small molecule inhibitors is a rapidly emerging therapeutic approach as evidenced by the recent approval of the first selective mutant IDH2 inhibitor AG-221 (enasidenib) for the treatment of IDH2-mutated AML. This review will focus on mutant isocitrate dehydrogenase as a therapeutic drug target and provides an update on selective and pan-mutant IDH1/2 inhibitors in clinical trials and other mutant IDH inhibitors that are under development.


Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Isocitrate Dehydrogenase/genetics , Mutant Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Neoplasms/enzymology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biocatalysis/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Isocitrate Dehydrogenase/antagonists & inhibitors , Isocitrate Dehydrogenase/metabolism , Molecular Structure , Mutant Proteins/genetics , Mutant Proteins/metabolism , Mutation , Neoplasms/pathology
9.
Eur J Med Chem ; 139: 573-586, 2017 Oct 20.
Article in English | MEDLINE | ID: mdl-28837922

ABSTRACT

Cancer cells consume more glucose to fuel metabolic programs fundamental to sustaining their survival, growth and proliferation. Among the fourteen SLC2A family members, GLUTs 1 and 4 are high-affinity glucose transporters. GLUT4 (SLC2A4) is highly expressed in muscle and adipose tissue. Basally retained within the cell, GLUT4 traffics to the plasma membrane (PM) in response to insulin and exercise-stimulation. The plasma cell malignancy multiple myeloma (MM) exhibits increased constitutive expression of GLUT4 on the PM, co-opting use of GLUT4 for survival and proliferation. GLUT4 inhibition by knockdown or treatment with the FDA-approved HIV protease inhibitor ritonavir leads to cytostatic and/or cytotoxic and chemosensitizing effects in tumor cells both in vitro and in vivo. We recently reported our generation of GLUT4 homology models and virtual high-throughput screening (vHTS) to identify multiple series of novel GLUT4 antagonists. In this report, we describe our initial hit-to-lead optimization to synthesize new analogs with improved potency and selectivity for GLUT4, and the biological characterization of these compounds in a variety of assays. We show that our lead compound (compound 20) decreases glucose uptake and cell proliferation as well as inhibits the expression of pro-survival MCL-1 in MM similar to the effect observed via knockdown of GLUT4 expression. Compound 20 is also effective at chemosensitizing multiple myeloma cell lines and patient samples to venetoclax, dexamethasone and melphalan. In sum, we report development of selective GLUT4 inhibitors lacking inhibitory activity against GLUT1 and GLUT8. We show that selective pharmacological inhibition of GLUT4 is feasible and this may represent a novel strategy for the treatment and chemosensitization of multiple myeloma to standard therapeutics.


Subject(s)
Antineoplastic Agents/pharmacology , Glucose Transporter Type 4/antagonists & inhibitors , Multiple Myeloma/drug therapy , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Death/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Glucose Transporter Type 4/metabolism , HEK293 Cells , Humans , Mice , Molecular Structure , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Structure-Activity Relationship , Tumor Cells, Cultured
10.
Bioorg Med Chem ; 24(21): 5088-5102, 2016 11 01.
Article in English | MEDLINE | ID: mdl-27591013

ABSTRACT

Our ongoing drug development endeavor to design compounds for symptomatic and neuroprotective treatment of Parkinson's disease (PD) led us to carry out a structure activity relationship study based on dopamine agonists pramipexole and 5-OHDPAT. Our goal was to incorporate structural elements in these agonists in a way to preserve their agonist activity while producing inhibitory activity against aggregation of α-synuclein protein. In our design we appended various catechol and related phenol derivatives to the parent agonists via different linker lengths. Structural optimization led to development of several potent agonists among which (-)-8a, (-)-14 and (-)-20 exhibited potent neuroprotective properties in a cellular PD model involving neurotoxin 6-OHDA. The lead compounds (-)-8a and (-)-14 were able to modulate aggregation of α-synuclein protein efficiently. Finally, in an in vivo PD animal model, compound (-)-8a exhibited efficacious anti-parkinsonian effect.


Subject(s)
Dopamine Agonists/pharmacology , Neuroprotective Agents/pharmacology , Receptors, Dopamine D2/agonists , Receptors, Dopamine D3/agonists , alpha-Synuclein/antagonists & inhibitors , Animals , Cell Survival/drug effects , Dopamine Agonists/chemical synthesis , Dopamine Agonists/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Oxidopamine/toxicity , PC12 Cells , Protein Aggregates/drug effects , Rats , Structure-Activity Relationship , alpha-Synuclein/metabolism
11.
Future Med Chem ; 7(17): 2385-406, 2015.
Article in English | MEDLINE | ID: mdl-26619226

ABSTRACT

The current therapy for depression is less than ideal with remission rates of only 25-35% and a slow onset of action with other associated side effects. The persistence of anhedonia originating from depressed dopaminergic activity is one of the most treatment-resistant symptoms of depression. Therefore, it has been hypothesized that triple reuptake inhibitors (TRIs) with potency to block dopamine reuptake in addition to serotonin and norepinephrine transporters should produce higher efficacy. The current review comprehensively describes the development of TRIs and discusses the importance of evaluation of in vivo transporter occupancy of TRIs, which should correlate with efficacy in humans.


Subject(s)
Antidepressive Agents/chemistry , Neurotransmitter Uptake Inhibitors/chemistry , Animals , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Depressive Disorder/drug therapy , Drug Evaluation, Preclinical , Humans , Maze Learning/drug effects , Neurotransmitter Uptake Inhibitors/pharmacology , Neurotransmitter Uptake Inhibitors/therapeutic use
12.
Bioorg Med Chem ; 23(4): 821-8, 2015 Feb 15.
Article in English | MEDLINE | ID: mdl-25593099

ABSTRACT

Current therapy of depression is less than ideal with remission rates of only 25-35% and response rates of 45-60%. It has been hypothesized that a dysfunctional dopaminergic system in the mesocorticolimbic pathway in depressive disorder may lead to development of anhedonia associated with loss of pleasure and interest along with loss of motivation. The current antidepressants do not address dopamine dysfunction which might explain their low efficacy. In this report, we have described an SAR study on our pyran-based triple reuptake inhibitors (TRIs) which are being investigated as the next-generation antidepressants. In the present work we demonstrate that our lead TRIs can be modified with appropriate aromatic substitutions to display a highly potent SSRI profile for compounds 2a and 4a (Ki (SERT); 0.71 and 2.68nM, respectively) or a potent DNRI profile for compounds 6b and 6h (Ki (DAT/NET); 8.94/4.76 and 13/7.37nM, respectively). Compounds 4g-4i exhibited potencies at all three monoamine transporters. The results provide insights into the structural requirements for developing selective dual- and triple-uptake inhibitors from a unique pyran molecular template for an effective management of depression and related disorders.


Subject(s)
Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacology , Norepinephrine/metabolism , Pyrans/chemistry , Pyrans/pharmacology , Benzylamines/chemistry , Benzylamines/pharmacology , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , Humans , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism
13.
Biomed Chromatogr ; 29(5): 654-63, 2015 May.
Article in English | MEDLINE | ID: mdl-25294254

ABSTRACT

There is an increasing interest in targeting the MDM2 oncogene for cancer therapy. SP-141, a novel designed small molecule MDM2 inhibitor, exerts excellent in vitro and in vivo anticancer activity. To facilitate the preclinical development of this candidate anticancer agent, we have developed an HPLC method for the quantitative analysis of SP-141. The method was validated to be precise, accurate, and specific, with a linear range of 16.2-32,400 ng/mL in plasma, 16.2-6480 ng/mL in homogenates of brain, heart, liver, kidneys, lungs, muscle and tumor, and 32.4-6480 ng/mL in spleen homogenates. The lower limit of quantification was 16.2 ng/mL in plasma and all the tissue homogenates, except for spleen homogenates, where it was 32.4 ng/mL. The intra- and inter-assay precisions (coefficient of variation) were between 0.86 and 13.39%, and accuracies (relative errors) ranged from -8.50 to 13.92%. The relative recoveries were 85.6-113.38%. SP-141 was stable in mouse plasma, modestly plasma bound and metabolized by S9 microsomal enzymes. We performed an initial pharmacokinetic study in tumor-bearing nude mice, demonstrating that SP-141 has a short half-life in plasma and wide tissue distribution. In summary, this HPLC method can be used in future preclinical and clinical investigations of SP-141.


Subject(s)
Antineoplastic Agents/blood , Chromatography, High Pressure Liquid/methods , Indoles/blood , Neoplasms/drug therapy , Pyridines/blood , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Female , Half-Life , Humans , Indoles/administration & dosage , Indoles/pharmacokinetics , Mice , Mice, Nude , Neoplasms/blood , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Tissue Distribution
14.
PLoS One ; 9(11): e113420, 2014.
Article in English | MEDLINE | ID: mdl-25427177

ABSTRACT

Major depressive disorder (MDD) is a debilitating disease affecting a wide cross section of people around the world. The current therapy for depression is less than adequate and there is a considerable unmet need for more efficacious treatment. Dopamine has been shown to play a significant role in depression including production of anhedonia which has been one of the untreated symptoms in MDD. It has been hypothesized that drugs acting at all three monoamine transporters including dopamine transporter should provide more efficacious antidepressants activity. This has led to the development of triple reuptake inhibitor D-473 which is a novel pyran based molecule and interacts with all three monoamine transporters. The monoamine uptake inhibition activity in the cloned human transporters expressed in HEK-293 cells (70.4, 9.18 and 39.7 for DAT, SERT and NET, respectively) indicates a serotonin preferring triple reuptake inhibition profile for this drug. The drug D-473 exhibited good brain penetration and produced efficacious activity in rat forced swim test under oral administration. The optimal efficacy dose did not produce any locomotor activation. Microdialysis experiment demonstrated that systemic administration of D-473 elevated extracellular level of the three monoamines DA, 5-HT, and NE efficaciously in the dorsal lateral striatum (DLS) and the medial prefrontal cortex (mPFC) area, indicating in vivo blockade of all three monoamine transporters by D-473. Thus, the current biological data from D-473 indicate potent antidepressant activity of the molecule.


Subject(s)
Amino Sugars/pharmacology , Antidepressive Agents/pharmacology , Benzylamines/pharmacology , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Uptake Inhibitors/pharmacology , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Pyrans/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Plasma Membrane Transport Proteins/metabolism , Administration, Oral , Amino Sugars/chemical synthesis , Amino Sugars/pharmacokinetics , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacokinetics , Behavior, Animal/drug effects , Benzylamines/chemical synthesis , Benzylamines/pharmacokinetics , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/metabolism , Depressive Disorder, Major/physiopathology , Dopamine/metabolism , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/pharmacokinetics , HEK293 Cells , Humans , Male , Norepinephrine/metabolism , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Pyrans/chemical synthesis , Pyrans/pharmacokinetics , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Swimming
15.
Nat Commun ; 5: 5086, 2014 Oct 01.
Article in English | MEDLINE | ID: mdl-25271708

ABSTRACT

A requirement for Mouse Double Minute 2 (MDM2) oncogene activation has been suggested to be associated with cancer progression and metastasis, including breast cancer. To date, most MDM2 inhibitors have been designed to block the MDM2-p53-binding interphase, and have low or no efficacy against advanced breast cancer with mutant or deficient p53. Here we use a high-throughput screening and computer-aided, structure-based rational drug design, and identify a lead compound, SP-141, which can directly bind to MDM2, inhibit MDM2 expression and induce its autoubiquitination and proteasomal degradation. SP-141 has strong in vitro and in vivo antibreast cancer activity, with no apparent host toxicity. While further investigation is needed, our data indicate that SP-141 is a novel targeted therapeutic agent that may especially benefit patients with advanced disease.


Subject(s)
Antineoplastic Agents/administration & dosage , Breast Neoplasms/drug therapy , Indoles/administration & dosage , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Pyridines/administration & dosage , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Drug Design , Female , Humans , Mice , Mice, Nude , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
16.
Medchemcomm ; 5(9): 1384-1399, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-25221669

ABSTRACT

To gain insights into the structural requirements for dopamine D2 and D3 agonists in the treatment of Parkinson's disease (PD) and to elucidate the basis of selectivity for D3 over D2 (D2/D3), 3D quantitative structure-activity relationship (3D QSAR) investigations using CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) methods were performed on a series of 45 structurally related D2 and D3 dopaminergic ligands. Two alignment methods (atom-based and flexible) and two charge calculation methods (Gasteiger-Hückel and AM1) were used in the present study. Overall, D2 affinity and selectivity (D2/D3) models performed better with r2cv values of 0.71 and 0.63 for CoMFA and 0.71 and 0.79 for CoMSIA, respectively. The corresponding predictive r2 values for the CoMFA and CoMSIA models were 0.92 and 0.86 and 0.91 and 0.78, respectively. The CoMFA models generated using flexible alignment outperformed the models with the atom-based alignment in terms of relevant statistics and interpretability of the generated contour maps while CoMSIA models obtained using atom-based alignment showed superiority in terms of internal and external predictive abilities. The presence of carbonyl group (C=O) attached to the piperazine ring and the hydrophobic biphenyl ring were found to be the most important features responsible for the D3 selectivity over D2. This study can be further utilized to design and develop selective and potent dopamine agonists to treat PD.

17.
Gastroenterology ; 147(4): 893-902.e2, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25016295

ABSTRACT

BACKGROUND & AIMS: The oncogene MDM2, which encodes an E3 ubiquitin ligase, is overexpressed in pancreatic cancers and is therefore a therapeutic target. Current inhibitors of MDM2 target the interaction between MDM2 and P53; these would have no effect on cancer cells that do not express full-length P53, including many pancreatic cancer cells. We searched for a compound that specifically inhibits MDM2 itself. METHODS: We performed a virtual screen and structure-based design to identify specific inhibitors of MDM2. We tested the activities of compounds identified on viability, proliferation, and protein levels of HPAC, Panc-1, AsPC-1, and Mia-Paca-2 pancreatic cancer cell lines. We tested whether intraperitoneal injections of one of the compounds identified affected growth of xenograft tumors from Panc-1 cells, or orthotopic tumors from Panc-1 and AsPC-1 cells (injected into pancreata), in nude mice. RESULTS: We identified a compound, called SP141, which bound directly to MDM2, promoting its auto-ubiquitination and degradation by the proteasome. The compound reduced levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation, with 50% inhibitory concentrations <0.5 µM (0.38-0.50 µM). Increasing concentrations of SP141 induced increasing levels of apoptosis and G2-M-phase arrest of pancreatic cancer cell lines, whether or not they expressed functional P53. Injection of nude mice with SP141 (40 mg/kg/d) inhibited growth of xenograft tumors (by 75% compared with control mice), and led to regression of orthotopic tumors. CONCLUSIONS: In a screen for specific inhibitors of MDM2, we identified a compound called SP141 that reduces levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation and ability to form tumors in nude mice. SP141 is a new class of MDM2 inhibitor that promotes MDM2 auto-ubiquitination and degradation. It might be further developed as a therapeutic agent for pancreatic cancer.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Pancreatic Neoplasms/drug therapy , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Pyridines/pharmacology , Adenocarcinoma/enzymology , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Design , Enzyme Inhibitors/chemistry , Female , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , Indoles/chemistry , Inhibitory Concentration 50 , Mice , Mice, Nude , Molecular Targeted Therapy , Pancreatic Neoplasms/enzymology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Proteasome Endopeptidase Complex/metabolism , Proteolysis , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , Pyridines/chemistry , Signal Transduction/drug effects , Structure-Activity Relationship , Time Factors , Transfection , Tumor Burden/drug effects , Ubiquitination , Xenograft Model Antitumor Assays
18.
Bioorg Med Chem ; 22(1): 311-24, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24315194

ABSTRACT

In this study we have generated a pharmacophore model of triple uptake inhibitor compounds based on novel asymmetric pyran derivatives and the newly developed asymmetric furan derivatives. The model revealed features important for inhibitors to exhibit a balanced activity against dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). In particular, a 'folded' conformation was found common to the active pyran compounds in the training set and was crucial to triple uptake inhibitory activity. Furthermore, the distances between the benzhydryl moiety and the N-benzyl group as well as the orientation of the secondary nitrogen were also important for TUI activity. We have validated our findings by synthesizing and testing novel asymmetric pyran analogs. The present work has also resulted in the discovery of a new series of asymmetric tetrahydrofuran derivatives as novel TUIs. Lead compounds 41 and 42 exhibited moderate TUI activity. Interestingly, the highest TUI activity by lead tetrahydrofuran compounds for example, 41 and 42, was exhibited in a stereochemical preference similar to pyran TUI for example, D-161.


Subject(s)
Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Depression/immunology , Neurotransmitter Uptake Inhibitors/chemistry , Pyrans/chemistry , Pyrans/pharmacology , Antidepressive Agents/metabolism , Biomimetics , Brain/metabolism , Computational Biology , Depression/drug therapy , Membrane Transport Proteins/metabolism , Molecular Conformation , Neurotransmitter Uptake Inhibitors/pharmacology , Pyrans/metabolism , Stereoisomerism , Structure-Activity Relationship
19.
Bioorg Med Chem Lett ; 23(22): 6146-51, 2013 Nov 15.
Article in English | MEDLINE | ID: mdl-24091080

ABSTRACT

In the present study we report the synthesis of halogen-substituted phenanthrene ß-diketo acids as new HIV-1 integrase inhibitors. The target phenanthrenes were obtained using both standard thermal- and microwave-assisted synthesis. 4-(6-Chlorophenanthren-2-yl)-2,4-dioxobutanoic acid (18) was the most active compound of the series, inhibiting both 3'-end processing (3'-P) and strand transfer (ST) with IC50 values of 5 and 1.3 µM, respectively. Docking studies revealed two predominant binding modes that were distinct from the binding modes of raltegravir and elvitegravir, and suggest a novel binding region in the IN active site. Moreover, these compounds are predicted not to interact significantly with some of the key amino acids (Q148 and N155) implicated in viral resistance. Therefore, this series of compounds can further be investigated for a possible chemotype to circumvent resistance to clinical HIV-1 IN inhibitors.


Subject(s)
HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV-1/enzymology , Keto Acids/chemistry , Keto Acids/pharmacology , Phenanthrenes/chemistry , Phenanthrenes/pharmacology , Drug Design , HIV Integrase Inhibitors/chemical synthesis , HIV-1/drug effects , Humans , Keto Acids/chemical synthesis , Models, Molecular , Molecular Docking Simulation , Phenanthrenes/chemical synthesis , Structure-Activity Relationship
20.
PLoS One ; 7(4): e34303, 2012.
Article in English | MEDLINE | ID: mdl-22558087

ABSTRACT

JKA97, a benzylidene analog of harmine, has been found to be a promising drug candidate for human cancer therapy, although the underlying molecular mechanisms have not been fully demonstrated. In this study, we evaluated the effects of JKA97 on human breast cancer cells in vitro and in vivo. JKA97 inhibited the growth and proliferation of MCF7 (p53 wild-type), MCF7 (p53 knockdown), and MDA-MB-468 (p53 mutant) cells in a dose-dependent manner. Treatment with JKA97 arrested breast cancer cells in G1 phase and induced apoptosis. JKA97 also significantly suppressed the growth of MCF7 and MDA-MB-468 xenograft tumors. It regulated the expression levels of G1 phase regulators, such as p21, p27, cyclinE, and cylinD1. JKA97 activated p21 transcription, independent of p53, but had little effect on p21 protein stability/degradation. In summary, our results suggest that JKA97 inhibits human breast cancer cell growth through activating p21, independent of p53, which provides a basis for developing this compound as a novel drug for human breast cancer therapy.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzylidene Compounds/pharmacology , Breast Neoplasms/metabolism , Carbolines/pharmacology , Cyclin-Dependent Kinase Inhibitor p21/metabolism , G1 Phase Cell Cycle Checkpoints/drug effects , Gene Expression Regulation/drug effects , Styrenes/pharmacology , Antineoplastic Agents/chemistry , Benzylidene Compounds/chemistry , Breast Neoplasms/drug therapy , Carbolines/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Female , Harmine/chemistry , Humans , In Vitro Techniques , Styrenes/chemistry
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