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1.
Proc Natl Acad Sci U S A ; 107(9): 4299-304, 2010 Mar 02.
Article in English | MEDLINE | ID: mdl-20154271

ABSTRACT

Kinases are known to regulate fundamental processes in cancer including tumor proliferation, metastasis, neovascularization, and chemoresistance. Accordingly, kinase inhibitors have been a major focus of drug development, and several kinase inhibitors are now approved for various cancer indications. Typically, kinase inhibitors are selected via high-throughput screening using catalytic kinase domains at low ATP concentration, and this process often yields ATP mimetics that lack specificity and/or function poorly in cells where ATP levels are high. Molecules targeting the allosteric site in the inactive kinase conformation (type II inhibitors) provide an alternative for developing selective inhibitors that are physiologically active. By applying a rational design approach using a constrained amino-triazole scaffold predicted to stabilize kinases in the inactive state, we generated a series of selective type II inhibitors of PDGFRbeta and B-RAF, important targets for pericyte recruitment and endothelial cell survival, respectively. These molecules were designed in silico and screened for antivascular activity in both cell-based models and a Tg(fli1-EGFP) zebrafish embryogenesis model. Dual inhibition of PDGFRbeta and B-RAF cellular signaling demonstrated synergistic antiangiogenic activity in both zebrafish and murine models of angiogenesis, and a combination of previously characterized PDGFRbeta and RAF inhibitors validated the synergy. Our lead compound was selected as an orally active molecule with favorable pharmacokinetic properties which demonstrated target inhibition in vivo leading to suppression of murine orthotopic tumors in both the kidney and pancreas.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Carcinoma, Renal Cell/pathology , Cell Division/drug effects , Kidney Neoplasms/pathology , Neovascularization, Pathologic , Pancreatic Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/metabolism , Receptor, Platelet-Derived Growth Factor beta/metabolism , Administration, Oral , Angiogenesis Inhibitors/therapeutic use , Animals , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/drug therapy , Kidney Neoplasms/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Protein Kinase Inhibitors/therapeutic use , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Zebrafish
2.
J Pharmacol Exp Ther ; 328(3): 758-65, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19056934

ABSTRACT

Phosphatidylinositol 3-kinases (PI3Ks) are key elements in the signaling cascades that lie downstream of many cellular receptors. In particular, PI3K delta and gamma isoforms contribute to inflammatory cell recruitment and subsequent activation. For this reason, in a series of preclinical studies, we tested the potential of a recently developed small-molecule inhibitor of these two isoforms, TG100-115 [3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol], as a form of anti-inflammatory therapy for respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). To determine pharmacokinetic profiles, aerosolized formulations of the drug were delivered to mice by a nose-only inhalation route, yielding high pulmonary TG100-115 levels with minimal systemic exposure. Safety assessments were favorable, with no clinical or histological changes noted after 21 days of daily dosing. In a murine asthma model, aerosolized TG100-115 markedly reduced the pulmonary eosinophilia and the concomitant interleukin-13 and mucin accumulation characteristic of this disease. As a functional benefit, interventional dosing schedules of this inhibitor also reduced airway hyper-responsiveness. To model the pulmonary neutrophilia characteristic of COPD, mice were exposed to either intranasal lipopolysaccharide or inhaled smoke. Aerosolized TG100-115 again inhibited these inflammatory patterns, most notably in the smoke model, where interventional therapy overcame the steroid-resistant nature of the pulmonary inflammation. In conclusion, aerosolized TG100-115 displays pharmacokinetic, safety, and biological activity profiles favorable for further development as a therapy for both asthma and COPD. Furthermore, these studies support the hypothesis that PI3K delta and gamma are suitable molecular targets for these diseases.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Asthma/drug therapy , Phenols/therapeutic use , Pteridines/therapeutic use , Pulmonary Disease, Chronic Obstructive/drug therapy , Administration, Intranasal , Aerosols , Animals , Anti-Inflammatory Agents/administration & dosage , Bronchial Hyperreactivity/drug therapy , Class Ib Phosphatidylinositol 3-Kinase , Disease Models, Animal , Isoenzymes/metabolism , Lipopolysaccharides/administration & dosage , Lipopolysaccharides/toxicity , Mice , Neutrophils/drug effects , Neutrophils/physiology , Phosphatidylinositol 3-Kinases/metabolism
3.
Expert Opin Drug Discov ; 4(1): 33-49, 2009 Jan.
Article in English | MEDLINE | ID: mdl-23480335

ABSTRACT

BACKGROUND: The synthesis of novel benzotriazine heterocycles was developed independently around the same time by Bischler, Bamberger and Arndt. Over the years, different groups have reported the synthesis of benzotriazine based compounds. OBJECTIVE: This literature review gives an update on recent benzotriazine compounds and their applications. CONCLUSION: The benzotriazine core has been used in various drug discovery projects including anticancer, anti-inflammatory and antimalarial programs. Recently, the benzotriazine core was used to develop selective kinase inhibitors targeting SRC, VEGFr2, BCR-ABL and BCR-ABL-T315I. Two benzotriazine based compounds, tirapazamine for the treatment of cancer and TG100801 for the treatment of age-related macular degeneration, have entered clinical trials.

4.
Curr Top Med Chem ; 8(10): 905-21, 2008.
Article in English | MEDLINE | ID: mdl-18673174

ABSTRACT

Chronic myelogenous leukemia (CML) is a hematological stem cell disorder caused by increased and unregulated growth of myeloid cells in the bone marrow, and the accumulation of excessive white blood cells. Abelson tyrosine kinase (ABL) is a non-receptor tyrosine kinase involved in cell growth and proliferation and is usually under tight control. However, 95% of CML patients have the ABL gene from chromosome 9 fused with the breakpoint cluster (BCR) gene from chromosome 22, resulting in a short chromosome known as the Philadelphia chromosome. This Philadelphia chromosome is responsible for the production of BCR-ABL, a constitutively active tyrosine kinase that causes uncontrolled cellular proliferation. An ABL inhibitor, imatinib, was approved by the FDA for the treatment of CML, and is currently used as first line therapy. However, a high percentage of clinical relapse has been observed due to long term treatment with imatinib. A majority of these relapsed patients have several point mutations at and around the ATP binding pocket of the ABL kinase domain in BCR-ABL. In order to address the resistance of mutated BCR-ABL to imatinib, 2(nd) generation inhibitors such as dasatinib, and nilotinib were developed. These compounds were approved for the treatment of CML patients who are resistant to imatinib. All of the BCR-ABL mutants are inhibited by the 2(nd) generation inhibitors with the exception of the T315I mutant. Several 3(rd) generation inhibitors such as AP24534, VX-680 (MK-0457), PHA-739358, PPY-A, XL-228, SGX-70393, FTY720 and TG101113 are being developed to target the T315I mutation. The early results from these compounds are encouraging and it is anticipated that physicians will have additional drugs at their disposal for the treatment of patients with the mutated BCR-ABL-T315I. The success of these inhibitors has greater implication not only in CML, but also in other diseases driven by kinases where the mutated gatekeeper residue plays a major role.


Subject(s)
Antineoplastic Agents/pharmacology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Proto-Oncogene Proteins c-abl/antagonists & inhibitors , Proto-Oncogene Proteins c-abl/genetics , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Molecular Structure , Structure-Activity Relationship
5.
J Med Chem ; 50(18): 4279-94, 2007 Sep 06.
Article in English | MEDLINE | ID: mdl-17685602

ABSTRACT

In studies aimed toward identifying effective and safe inhibitors of kinase signaling cascades that underlie ischemia/reperfusion (I/R) injury, we synthesized a series of pteridines and pyridopyrazines. The design strategy was inspired by the examination of naturally occurring PI3K inhibitors such as wortmannin and quercetin, and building a pharmacophore-based model used for optimization. Structural modifications led to hybrid molecules which incorporated aminopyrimidine and aminopyridine moieties with ATP mimetic characteristics into the pharmacophore motifs to modulate kinase affinity and selectivity. Elaborations involving substitutions of the 2 and 4 positions of the pyrimidine or pyridine ring and the 6 and 7 positions of the central pyrazine ring resulted in in vivo activity profiles which identified potent inhibitors of vascular endothelial growth factor (VEGF) induced vascular leakage. Pathway analysis identified a diaminopteridine-diphenol as a potent and selective phosphatidylinositol-3-kinase (PI3K) inhibitor. The structure-activity relationship studies of various analogues of diaminopteridine-diphenol-based on biochemical assays resulted in potent inhibitors of PI3K.


Subject(s)
Myocardial Infarction/complications , Myocardial Reperfusion Injury/drug therapy , Phenols/chemical synthesis , Phosphoinositide-3 Kinase Inhibitors , Pteridines/chemical synthesis , Animals , Antigens, CD/metabolism , Cadherins/metabolism , Capillary Permeability/drug effects , Cell Proliferation , Cells, Cultured , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Humans , Isoenzymes/antagonists & inhibitors , Male , Models, Molecular , Myocardial Reperfusion Injury/etiology , Phenols/pharmacokinetics , Phenols/pharmacology , Phosphorylation , Pteridines/pharmacokinetics , Pteridines/pharmacology , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Umbilical Veins/cytology , Vascular Endothelial Growth Factor A/pharmacology
6.
Bioorg Med Chem Lett ; 17(3): 602-8, 2007 Feb 01.
Article in English | MEDLINE | ID: mdl-17113292
7.
Proc Natl Acad Sci U S A ; 103(52): 19866-71, 2006 Dec 26.
Article in English | MEDLINE | ID: mdl-17172449

ABSTRACT

Although phosphoinositide 3-kinases (PI3Ks) play beneficial pro-cell survival roles during tissue ischemia, some isoforms (gamma and delta) paradoxically contribute to the inflammation that damages these same tissues upon reperfusion. We therefore considered the possibility that selectively inhibiting proinflammatory PI3K isoforms during the reperfusion phase could ultimately limit overall tissue damage seen in ischemia/reperfusion injuries such as myocardial infarction. Panreactive and isoform-restricted PI3K inhibitors were identified by screening a novel chemical family; molecular modeling studies attributed isoform specificity based on rotational freedom of substituent groups. One compound (TG100-115) identified as a selective PI3K gamma/delta inhibitor potently inhibited edema and inflammation in response to multiple mediators known to participate in myocardial infarction, including vascular endothelial growth factor and platelet-activating factor; by contrast, endothelial cell mitogenesis, a repair process important to tissue survival after ischemic damage, was not disrupted. In rigorous animal MI models, TG100-115 provided potent cardioprotection, reducing infarct development and preserving myocardial function. Importantly, this was achieved when dosing well after myocardial reperfusion (up to 3 h after), the same time period when patients are most accessible for therapeutic intervention. In conclusion, by targeting pathologic events occurring relatively late in myocardial damage, we have identified a potential means of addressing an elusive clinical goal: meaningful cardioprotection in the postreperfusion time period.


Subject(s)
Myocardial Ischemia/enzymology , Myocardial Ischemia/pathology , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Reperfusion Injury/enzymology , Reperfusion Injury/pathology , Animals , Cell Proliferation , Cells, Cultured , Disease Models, Animal , Humans , Inflammation/drug therapy , Inflammation/enzymology , Inflammation/pathology , Intercellular Signaling Peptides and Proteins/metabolism , Models, Molecular , Myocardial Ischemia/drug therapy , Myocardial Ischemia/genetics , Phosphatidylinositol 3-Kinases/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Protein Subunits/antagonists & inhibitors , Protein Subunits/chemistry , Protein Subunits/metabolism , Rats , Reperfusion Injury/drug therapy , Reperfusion Injury/genetics , Signal Transduction , Swine
8.
Bioorg Med Chem Lett ; 16(21): 5546-50, 2006 Nov 01.
Article in English | MEDLINE | ID: mdl-16931012

ABSTRACT

We report the discovery and preliminary SAR studies of a series of structurally novel benzotriazine core based small molecules as inhibitors of Src kinase. To the best of our knowledge, benzotriazine template based compounds have not been reported as kinase inhibitors. The 3-(2-(1-pyrrolidinyl)ethoxy)phenyl analogue (43) was identified as one of the most potent inhibitors of Src kinase.


Subject(s)
Proto-Oncogene Proteins pp60(c-src)/antagonists & inhibitors , Triazines/pharmacology , Humans , Structure-Activity Relationship
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