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1.
J Biol Chem ; 288(37): 26926-43, 2013 Sep 13.
Article in English | MEDLINE | ID: mdl-23897821

ABSTRACT

Histone deacetylases (HDACs) are critical in the control of gene expression, and dysregulation of their activity has been implicated in a broad range of diseases, including cancer, cardiovascular, and neurological diseases. HDAC inhibitors (HDACi) employing different zinc chelating functionalities such as hydroxamic acids and benzamides have shown promising results in cancer therapy. Although it has also been suggested that HDACi with increased isozyme selectivity and potency may broaden their clinical utility and minimize side effects, the translation of this idea to the clinic remains to be investigated. Moreover, a detailed understanding of how HDACi with different pharmacological properties affect biological functions in vitro and in vivo is still missing. Here, we show that a panel of benzamide-containing HDACi are slow tight-binding inhibitors with long residence times unlike the hydroxamate-containing HDACi vorinostat and trichostatin-A. Characterization of changes in H2BK5 and H4K14 acetylation following HDACi treatment in the neuroblastoma cell line SH-SY5Y revealed that the timing and magnitude of histone acetylation mirrored both the association and dissociation kinetic rates of the inhibitors. In contrast, cell viability and microarray gene expression analysis indicated that cell death induction and changes in transcriptional regulation do not correlate with the dissociation kinetic rates of the HDACi. Therefore, our study suggests that determining how the selective and kinetic inhibition properties of HDACi affect cell function will help to evaluate their therapeutic utility.


Subject(s)
Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Histone Deacetylase Inhibitors/chemistry , Histones/chemistry , Acetylation , Benzamides/chemistry , Binding, Competitive , Cell Line, Tumor , Cell Survival/drug effects , Humans , Hydroxamic Acids/chemistry , Inhibitory Concentration 50 , Kinetics , Oligonucleotide Array Sequence Analysis , Protein Binding , Pyridines/chemistry , Transcription, Genetic , Vorinostat
2.
J Med Chem ; 54(22): 7815-33, 2011 Nov 24.
Article in English | MEDLINE | ID: mdl-21985639

ABSTRACT

Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3Kα has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3Kα vs PI3Kß selectivity for two chemical series. In the thienopyrimidine series of inhibitors, we propose that select ligands achieve selectivity derived from a hydrogen bonding interaction with Arg770 of PI3Kα that is not attained with the corresponding Lys777 of PI3Kß. In the benzoxepin series of inhibitors, the selectivity observed can be rationalized by the difference in electrostatic potential between the two isoforms in a given region rather than any specific interaction.


Subject(s)
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Models, Molecular , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Benzoxepins/chemistry , Benzoxepins/pharmacokinetics , Benzoxepins/pharmacology , Cell Line, Tumor , Class I Phosphatidylinositol 3-Kinases/chemistry , Crystallography, X-Ray , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Hydrogen Bonding , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Mice , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Conformation , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship
3.
J Med Chem ; 54(21): 7579-87, 2011 Nov 10.
Article in English | MEDLINE | ID: mdl-21981714

ABSTRACT

The discovery of 2 (GDC-0980), a class I PI3K and mTOR kinase inhibitor for oncology indications, is described. mTOR inhibition was added to the class I PI3K inhibitor 1 (GDC-0941) scaffold primarily through the substitution of the indazole in 1 for a 2-aminopyrimidine. This substitution also increased the microsomal stability and the free fraction of compounds as evidenced through a pairwise comparison of molecules that were otherwise identical. Highlighted in detail are analogues of an advanced compound 4 that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC(50)s of 5, 27, 7, and 14 nM for PI3Kα, ß, δ, and γ, respectively, inhibits mTOR with a K(i) of 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer.


Subject(s)
Antineoplastic Agents/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Pyrimidines/chemical synthesis , TOR Serine-Threonine Kinases/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , In Vitro Techniques , Isoenzymes/antagonists & inhibitors , Mice , Mice, Nude , Microsomes, Liver/metabolism , Models, Molecular , Neoplasm Transplantation , Protein Conformation , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Transplantation, Heterologous
4.
Bioorg Med Chem Lett ; 20(22): 6748-53, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20875741

ABSTRACT

Potent and efficacious inhibitors of the hedgehog pathway for the treatment of cancer have been prepared using the 2-pyridyl biphenyl amide scaffold common to the clinical lead GDC-0449. Analogs with polar groups in the para-position of the aryl amide ring optimized potency, had minimal CYP inhibition, and possessed good exposure in rats. Compounds 9d and 14f potently inhibited hedgehog signaling as measured by Gli1 mRNA and were found to be equivalent or more potent than GDC-0449, respectively, when studied in a Ptch(+/-) medulloblastoma allograft model, that is, highly dependent on hedgehog signaling.


Subject(s)
Amides/chemistry , Hedgehog Proteins/antagonists & inhibitors , Pyridines/pharmacology , Animals , Drug Screening Assays, Antitumor , Hedgehog Proteins/metabolism , Mice , Pyridines/chemistry , Pyridines/pharmacokinetics , Rats , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 20(8): 2408-11, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20346656

ABSTRACT

Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor.


Subject(s)
Enzyme Inhibitors/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , Thiophenes/pharmacology , Animals , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Female , Mice , Pyrimidines/chemistry , Rats , TOR Serine-Threonine Kinases , Thiophenes/chemistry
6.
Bioorg Med Chem Lett ; 19(19): 5576-81, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19716296

ABSTRACT

SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.


Subject(s)
Amides/chemistry , Anilides/chemistry , Hedgehog Proteins/metabolism , Pyridines/chemistry , Amides/chemical synthesis , Amides/pharmacology , Anilides/chemical synthesis , Anilides/pharmacology , Animals , Benzimidazoles/chemistry , Carcinoma, Basal Cell/drug therapy , Cell Line , Cerebellar Neoplasms/drug therapy , Hedgehog Proteins/antagonists & inhibitors , Humans , Medulloblastoma/drug therapy , Mice , Mice, Nude , Pyridines/chemical synthesis , Pyridines/pharmacology , Signal Transduction , Structure-Activity Relationship , Xenograft Model Antitumor Assays
7.
PLoS One ; 3(8): e2930, 2008 Aug 13.
Article in English | MEDLINE | ID: mdl-18698373

ABSTRACT

Wnt signals exercise strong cell-biological and regenerative effects of considerable therapeutic value. There are, however, no specific Wnt agonists and no method for in vivo delivery of purified Wnt proteins. Wnts contain lipid adducts that are required for activity and we exploited this lipophilicity by packaging purified Wnt3a protein into lipid vesicles. Rather than being encapsulated, Wnts are tethered to the liposomal surface, where they enhance and sustain Wnt signaling in vitro. Molecules that effectively antagonize soluble Wnt3a protein but are ineffective against the Wnt3a signal presented by a cell in a paracrine or autocrine manner are also unable to block liposomal Wnt3a activity, suggesting that liposomal packaging mimics the biological state of active Wnts. When delivered subcutaneously, Wnt3a liposomes induce hair follicle neogenesis, demonstrating their robust biological activity in a regenerative context.


Subject(s)
Wnt Proteins/biosynthesis , Wnt Proteins/physiology , Animals , Cell Culture Techniques , Liposomes , Male , Membrane Lipids/physiology , Mice , Mice, Inbred Strains , Signal Transduction , Wnt Proteins/antagonists & inhibitors , Wnt Proteins/isolation & purification , Wnt3 Protein , Wnt3A Protein
8.
Bioorg Med Chem Lett ; 14(10): 2463-7, 2004 May 17.
Article in English | MEDLINE | ID: mdl-15109633

ABSTRACT

We have identified and synthesized a series of [1,2,4]triazolo[3,4-a]phthalazine derivatives as high-affinity ligands to alpha 2 delta-1 subunit of voltage gated calcium channels. Structure-activity relationship studies directed toward improving the potency and physical properties of 2 lead to the discovery of 20 (IC(50)=15 nM) and (S)-22 (IC(50)=30 nM). A potent and selective radioligand, [(3)H]-(S)-22 was also synthesized to demonstrate that this ligand binds to the same site as gabapentin.


Subject(s)
Calcium Channel Blockers/chemical synthesis , Calcium Channels/metabolism , Phthalazines/pharmacology , Amines/metabolism , Analgesics/chemical synthesis , Analgesics/pharmacology , Binding Sites , Calcium Channel Blockers/pharmacology , Cyclohexanecarboxylic Acids/metabolism , Gabapentin , Humans , Inhibitory Concentration 50 , Ligands , Phthalazines/chemical synthesis , Radioligand Assay , Structure-Activity Relationship , gamma-Aminobutyric Acid/metabolism
10.
J Am Chem Soc ; 124(35): 10396-415, 2002 Sep 04.
Article in English | MEDLINE | ID: mdl-12197742

ABSTRACT

The total synthesis of the novel antitumor agent callipeltoside A, as well as several analogues, is accomplished and allows assignment of the stereochemistry not previously established. A convergent strategy is employed wherein the target is dissected into three units-the core macrolactone, the sugar callipeltose, and a cyclopropyl bearing chain. The strategy for the synthesis of the macrolactone derives from employment of diastereoselective aldol reactions that emanate from an 11 carbon piece. The stereochemistry of the latter derives from the chiral pool and two asymmetric reactions-a ketone reduction using CBS-oxazaborolidine and a Pd catalyzed asymmetric allylic alkylation (AAA). The novelty of the latter protocol is its control of regioselectivity as well as absolute configuration. The trisubstituted olefin is generated using an alkene-alkyne coupling to create a trisubustituted olefin with complete control of geometry. The excellent chemo- and regioselectivity highlights the synthetic potential of this new ruthenium catalyzed process. The macrolactonization employs in situ formation of an acylketene generated by the thermolysis of a m-dioxolenone. Two strategies evolved for attachment of the side chain-one based upon olefination and a second upon olefin metathesis. The higher efficiency of the latter makes it the method of choice. A novel one pot olefin metathesis-Takai olefination protocol that should be broadly applicable is developed. The sugar is attached by a glycosylation by employing the O-trichloroacetimidate. This route provided both C-13 epimers of the macrolactone by using either enantiomeric ligand in the Pd AAA reaction. It also provided both trans-chlorocyclopropane diastereomers of callipeltoside A which allows the C-20 and C-21 configuration to be established as S and R, respectively. The convergent nature of the synthesis in which the largest piece, the macrolatone, require only 16 linear steps imparts utility to this strategy for the establishment of the structure-activity relationship. Initial biological testing demonstrates the irrelevance of the chloro substituent and the necessity of the sugar.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Antibiotics, Antineoplastic/chemical synthesis , Macrolides , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Female , Humans , Molecular Conformation , Ovarian Neoplasms/drug therapy , Stereoisomerism , Tumor Cells, Cultured
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