ABSTRACT
Cancer therapy reduces tumor burden via tumor cell death ("debris"), which can accelerate tumor progression via the failure of inflammation resolution. Thus, there is an urgent need to develop treatment modalities that stimulate the clearance or resolution of inflammation-associated debris. Here, we demonstrate that chemotherapy-generated debris stimulates metastasis by up-regulating soluble epoxide hydrolase (sEH) and the prostaglandin E2 receptor 4 (EP4). Therapy-induced tumor cell debris triggers a storm of proinflammatory and proangiogenic eicosanoid-driven cytokines. Thus, targeting a single eicosanoid or cytokine is unlikely to prevent chemotherapy-induced metastasis. Pharmacological abrogation of both sEH and EP4 eicosanoid pathways prevents hepato-pancreatic tumor growth and liver metastasis by promoting macrophage phagocytosis of debris and counterregulating a protumorigenic eicosanoid and cytokine storm. Therefore, stimulating the clearance of tumor cell debris via combined sEH and EP4 inhibition is an approach to prevent debris-stimulated metastasis and tumor growth.
Subject(s)
Eicosanoids/metabolism , Epoxide Hydrolases/biosynthesis , Macrophages/immunology , Neoplasm Metastasis/pathology , Receptors, Prostaglandin E, EP4 Subtype/biosynthesis , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/pathology , Cell Death/drug effects , Cell Line, Tumor , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Cytokines/metabolism , Hep G2 Cells , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Neoplasm Metastasis/prevention & control , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Phagocytosis/immunology , RAW 264.7 CellsABSTRACT
Activators of the pyruvate kinase M2 (PKM2) are currently attracting significant interest as potential anticancer therapies. They may achieve a novel antiproliferation response in cancer cells through modulation of the classic 'Warburg effect' characteristic of aberrant metabolism. In this Letter, we describe the optimization of a weakly active screening hit to a structurally novel series of small molecule 3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as potent PKM2 activators.
Subject(s)
Carrier Proteins/metabolism , Drug Discovery/methods , Membrane Proteins/metabolism , Pyrazoles/chemistry , Pyrazoles/metabolism , Thyroid Hormones/metabolism , Carrier Proteins/agonists , Enzyme Activation/drug effects , Enzyme Activation/physiology , Humans , Isoenzymes/metabolism , Membrane Proteins/agonists , Pyrazoles/pharmacology , Structure-Activity Relationship , Thyroid Hormones/agonists , Thyroid Hormone-Binding ProteinsABSTRACT
2-Arylamino-4-aryl-pyrimidines were found to be potent inhibitors of PAK1 kinase. The synthesis and SAR are described. The incorporation of a bromide at the 5-position of the pyrimidine core and in combination with a 1,2-dimethylpiperazine pendant domain yielded a lead compound with potent PAK1 inhibition and anti-proliferative activity in various colon cancer cell lines.
Subject(s)
Aniline Compounds/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Pyrimidinones/chemical synthesis , p21-Activated Kinases/antagonists & inhibitors , Aniline Compounds/chemistry , Aniline Compounds/toxicity , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/toxicity , Pyrimidinones/chemistry , Pyrimidinones/toxicity , Structure-Activity Relationship , p21-Activated Kinases/metabolismABSTRACT
A series of compounds based on a 4-phenyl-2-phenylaminopyridine scaffold that are potent and selective inhibitors of Traf2- and Nck-interacting kinase (TNIK) activity are described. These compounds were used as tools to test the importance of TNIK kinase activity in signaling and proliferation in Wnt-activated colorectal cancer cells. The results indicate that pharmacological inhibition of TNIK kinase activity has minimal effects on either Wnt/TCF4/ß-catenin-driven transcription or viability. The findings suggest that the kinase activity of TNIK may be less important to Wnt signaling than other aspects of TNIK function, such as its putative role in stabilizing the TCF4/ß-catenin transcriptional complex.
Subject(s)
Aminopyridines/chemical synthesis , Aminopyridines/pharmacology , Drug Discovery , Protein Serine-Threonine Kinases/antagonists & inhibitors , Aminopyridines/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Colorectal Neoplasms , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Signal Transduction/drug effectsABSTRACT
Limited treatment options exist for cancer within the bone, as demonstrated by the inevitable, pernicious course of metastatic and blood cancers. The difficulty of eliminating bone-residing cancer, especially drug-resistant cancer, necessitates novel, alternative treatments to manipulate tumor cells and their microenvironment, with minimal off-target effects. To this end, bone-targeted conjugate (BP-Btz) was generated by linking bortezomib (Btz, an anticancer, bone-stimulatory drug) to a bisphosphonate (BP, a targeting ligand) through a cleavable linker that enables spatiotemporally controlled delivery of Btz to bone under acidic conditions for treating multiple myeloma (MM). Three conjugates with different linkers were developed and screened for best efficacy in mouse model of MM. Results demonstrated that the lead candidate BP-Btz with optimal linker could overcome Btz resistance, reduced tumor burden, bone destruction, or tumor metastasis more effectively than BP or free Btz without thrombocytopenia and neurotoxicity in mice bearing myeloma. Furthermore, pharmacokinetic and pharmacodynamic studies showed that BP-Btz bound to bone matrix, released Btz in acidic conditions, and had a higher local concentration and longer half-life than Btz in bone. Our findings suggest the potential of bone-targeted Btz conjugate as an efficacious Btz-resistant MM treatment mechanism. © 2021 American Society for Bone and Mineral Research (ASBMR).
Subject(s)
Antineoplastic Agents , Bone Neoplasms , Multiple Myeloma , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Bone Neoplasms/drug therapy , Bone and Bones/pathology , Bortezomib/pharmacology , Bortezomib/therapeutic use , Cell Line, Tumor , Drug Resistance, Neoplasm , Mice , Multiple Myeloma/pathology , Tumor MicroenvironmentABSTRACT
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
Subject(s)
Acetamides/chemical synthesis , Antidiuretic Hormone Receptor Antagonists , Hypothalamo-Hypophyseal System/drug effects , Quinazolinones/chemical synthesis , Quinazolinones/pharmacology , Acetamides/chemistry , Acetamides/pharmacology , Animals , Caco-2 Cells , Humans , Inhibitory Concentration 50 , Male , Molecular Structure , Quinazolinones/chemistry , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.
Subject(s)
Amides/chemistry , Antihypertensive Agents/chemistry , Cyclohexanols/chemistry , Isoxazoles/chemistry , TRPV Cation Channels/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacokinetics , Cyclohexanols/chemical synthesis , Cyclohexanols/pharmacokinetics , Hyperthermia, Induced , Isoxazoles/chemical synthesis , Isoxazoles/pharmacokinetics , Rats , Rats, Wistar , Structure-Activity Relationship , TRPV Cation Channels/metabolismABSTRACT
High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.
Subject(s)
Receptors, Glucocorticoid/antagonists & inhibitors , Animals , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Humans , Hydrocortisone/chemistry , Microsomes/metabolism , Rats , Receptors, Glucocorticoid/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacokineticsABSTRACT
Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.
Subject(s)
Cyclohexanols/chemistry , Isoxazoles/chemistry , TRPV Cation Channels/antagonists & inhibitors , Administration, Oral , Amides/chemistry , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Capsaicin/toxicity , Cyclohexanols/pharmacokinetics , Cyclohexanols/therapeutic use , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Isoxazoles/pharmacokinetics , Isoxazoles/therapeutic use , Microsomes, Liver/metabolism , Rats , Structure-Activity Relationship , TRPV Cation Channels/metabolismABSTRACT
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) (V(3)) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Animals , Humans , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
The discovery, synthesis, and preliminary structure-activity relationship (SAR) of a novel class of vasopressin V3 (V1b) receptor antagonists is described. Compound 1, identified by high throughput screening of a diverse, three million-member compound collection, prepared using ECLiPS technology, had good activity in a V3 binding assay (IC50=0.20 microM), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC50=0.31 microM) and 24 (IC50=0.12 microM) with improved drug-like characteristics.
Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Antidiuretic Hormone Receptor Antagonists , Quinazolines/chemistry , Quinazolines/pharmacology , Receptors, Vasopressin/metabolism , Acetamides/chemical synthesis , Animals , Depressive Disorder/drug therapy , Humans , Quinazolines/chemical synthesis , Rats , Structure-Activity RelationshipABSTRACT
The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.
Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Indoles/chemistry , Indoles/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptor, Cannabinoid, CB1/metabolism , Animals , Benzimidazoles/metabolism , Benzimidazoles/pharmacokinetics , Humans , Hypothermia/chemically induced , Hypothermia/drug therapy , Indoles/metabolism , Indoles/pharmacokinetics , Male , Mice , Microsomes, Liver/metabolism , Obesity/drug therapy , Rats , Rats, Wistar , Solubility , Structure-Activity RelationshipABSTRACT
A novel series of quinolinone-based adenosine A(2B) receptor antagonists was identified via high throughput screening of an encoded combinatorial compound collection. Synthesis and assay of a series of analogs highlighted essential structural features of the initial hit. Optimization resulted in an A(2B) antagonist (2i) which exhibited potent activity in a cAMP accumulation assay (5.1 nM) and an IL-8 release assay (0.4 nM).
Subject(s)
Adenosine A2 Receptor Antagonists/chemistry , Quinolones/chemistry , Receptor, Adenosine A2B/chemistry , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/pharmacology , Combinatorial Chemistry Techniques , Drug Evaluation, Preclinical , Humans , Microsomes, Liver/metabolism , Quinolones/chemical synthesis , Quinolones/pharmacology , Receptor, Adenosine A2B/metabolism , Structure-Activity RelationshipABSTRACT
The chemokine receptor CXCR2 is involved in different inflammatory diseases, like chronic obstructive pulmonary disease, psoriasis, rheumatoid arthritis, and ulcerative colitis; therefore, it is considered an attractive drug target. Different classes of small CXCR2 antagonists have been developed. In this study, we selected seven CXCR2 antagonists from the diarylurea, imidazolylpyrimide, and thiazolopyrimidine class and studied their mechanisms of action at human CXCR2. All compounds are able to displace (125)I-CXCL8 and inhibit CXCL8-induced beta-arrestin2 recruitment. Detailed studies with representatives of each class showed that these compounds displace and antagonize CXCL8, most probably via a noncompetitive, allosteric mechanism. In addition, we radiolabeled the high-affinity CXCR2 antagonist SB265610 [1-(2-bromophenyl)-3-(4-cyano-1H-benzo[d] [1,2,3]-triazol-7-yl)urea] and subjected [(3)H]SB265610 to a detailed analysis. The binding of this radioligand was saturable and reversible. Using [(3)H]SB265610, we found that compounds of the different chemical classes bind to distinct binding sites. Hence, the use of a radiolabeled low-molecular weight CXCR2 antagonist serves as a tool to investigate the different binding sites of CXCR2 antagonists in more detail.
Subject(s)
Phenylurea Compounds/pharmacology , Receptors, Interleukin-8B/antagonists & inhibitors , Allosteric Site , Animals , Binding, Competitive , COS Cells , Chlorocebus aethiops , Humans , Phenylurea Compounds/chemistry , Protein Binding , Radioligand Assay , Structure-Activity Relationship , TransfectionABSTRACT
The profile of a series of triazine and pyrimidine based ROCK inhibitors is described. An initial binding mode was established based on a homology model and the proposed interactions are consistent with the observed SAR. Compounds from the series are potent in a cell migration assay and possess a favorable kinase selectivity. In vivo activity was demonstrated for compound 1A in a spontaneous hypertensive rat model.
Subject(s)
Antihypertensive Agents/chemistry , Hypertension/drug therapy , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Triazines/chemistry , rho-Associated Kinases/antagonists & inhibitors , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacology , Binding Sites , Computer Simulation , Disease Models, Animal , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/pharmacology , rho-Associated Kinases/metabolismABSTRACT
A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-gamma (INF-gamma) production.
Subject(s)
Benzimidazoles/pharmacology , Enzyme Inhibitors/pharmacology , Janus Kinase 3/antagonists & inhibitors , Purines/pharmacology , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Dose-Response Relationship, Drug , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Interferon-gamma/biosynthesis , Interleukin-2/antagonists & inhibitors , Mice , Models, Animal , Models, Molecular , Molecular Structure , Purines/chemical synthesis , Purines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Pim-1 has emerged as an attractive target for developing therapeutic agents for treating disorders involving abnormal cell growth, especially cancers. Herein we present lead optimization, chemical synthesis and biological evaluation of pyrazolo[1,5-a]pyrimidine compounds as potent and selective inhibitors of Pim-1 starting from a hit from virtual screening. These pyrazolo[1,5-a]pyrimidine compounds strongly inhibited Pim-1 and Flt-3 kinases. Selected compounds suppressed both the phosphorylation of BAD protein in a cell-based assay and 2-dimensional colony formation in a clonogenic cell survival assay at submicromolar potency, suggesting that cellular activity was mediated through inhibition of Pim-1. Moreover, these Pim-1 inhibitors did not show significant hERG inhibition at 30 µM concentration. The lead compound proved to be highly selective against a panel of 119 oncogenic kinases, indicating it had an improved safety profile compared with the first generation Pim-1 inhibitor SGI-1776.
ABSTRACT
The large-scale application of combinatorial chemistry to drug discovery is an endeavor that is now more than ten years old. The growth of chemical libraries together with the influx of novel genomic targets has led to a reconstruction of the drug-screening paradigm. The drug discovery industry faces a post-genomic world where the interplay between tens-of-thousands of proteins must be addressed. To compound this complexity, there now exists the ability to screen millions of compounds against a single target. This review focuses on the practice and use of selecting individual compounds from large chemical libraries that act on targets relevant to signal transduction.
Subject(s)
Combinatorial Chemistry Techniques/methods , Drug Delivery Systems/methods , Signal Transduction/drug effects , Animals , Humans , Signal Transduction/physiologyABSTRACT
The proto-oncogene proviral integration site for moloney murine leukemia virus (PIM) kinases (PIM-1, PIM-2, and PIM-3) are serine/threonine kinases that are involved in a number of signaling pathways important to cancer cells. PIM kinases act in downstream effector functions as inhibitors of apoptosis and as positive regulators of G1-S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, and prostate, gastric, and head and neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma and to assess the role PIM function in disease progression and their potential to serve as molecular targets for therapy. One hundred thirty-seven cases of urothelial carcinoma were included in this study of surgical biopsy and resection specimens. High levels of expression of all three PIM family members were observed in both noninvasive and invasive urothelial carcinomas. The second-generation PIM inhibitor, TP-3654, displays submicromolar activity in pharmacodynamic biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3 bladder cancer cell line. TP-3654 displays favorable human ether-à-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability. In vivo xenograft studies using a bladder cancer cell line show that PIM kinase inhibition can reduce tumor growth, suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Transitional Cell/enzymology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Urinary Bladder Neoplasms/enzymology , Animals , Blotting, Western , Female , Humans , Imidazoles/pharmacology , Male , Mice , Mice, Nude , Multiplex Polymerase Chain Reaction , Oligopeptides/pharmacology , Proto-Oncogene Mas , Pyridazines/pharmacology , RNA, Small Interfering , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Transduction, Genetic , Vasoactive Intestinal Peptide/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Inactivation of the M2 form of pyruvate kinase (PKM2) in cancer cells is associated with increased tumorigenicity. To test the hypothesis that tumor growth may be inhibited through the PKM2 pathway, we generated a series of small-molecule PKM2 activators. The compounds exhibited low nanomolar activity in both biochemical and cell-based PKM2 activity assays. These compounds did not affect the growth of cancer cell lines under normal conditions in vitro, but strongly inhibited the proliferation of multiple lung cancer cell lines when serine was absent from the cell culture media. In addition, PKM2 activators inhibited the growth of an aggressive lung adenocarcinoma xenograft. These findings show that PKM2 activation by small molecules influences the growth of cancer cells in vitro and in vivo, and suggest that such compounds may augment cancer therapies.