ABSTRACT
A family of thieno[3,2-b]pyridine based small molecule inhibitors of c-Met and VEGFR2 were designed based on lead structure 2. These compounds were shown to have IC(50) values in the low nanomolar range in vitro and were efficacious in human tumor xenograft models in mice in vivo.
Subject(s)
Antineoplastic Agents/chemistry , Malonates/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridines/chemistry , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Humans , Malonates/chemical synthesis , Malonates/pharmacokinetics , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacokineticsABSTRACT
Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2S,4S)-4-mercaptopyrrolidine-2-carboxylic acid, in 1a, was a good replacement for homocysteine, while the corresponding six-member counterpart was less active. Further optimization of 1a, changed the selectivity profile of these inhibitors. A Chloro substituent at the 2-position of 1a, compound 1d, retained potency against DNMT1, while N(6) alkylation, compound 7a, conserved DNMT3b2 activity. The concomitant substitutions of 1a at both 2- and N(6) positions reduced activity against both enzymes.
Subject(s)
DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Homocysteine/analogs & derivatives , Pyrrolidines/chemical synthesis , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Homocysteine/chemical synthesis , Homocysteine/pharmacology , Humans , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Structure-Activity RelationshipABSTRACT
The inhibitory activity of base-modified SAH analogues and the specificity of inhibiting human DNMT1 and DNMT3b2 enzymes was explored. The 6-amino group was essential while the 7-N of the adenine ring of SAH could be replaced by CH- without loss of activity against both enzymes. The introduction of small groups at the 2-position of the adenine moiety favors DNMT1 over DNMT3b2 inhibition whereas alkylation of the N(6)-amino moiety favors the inhibition of DNMT3b2 enzyme.
Subject(s)
DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , S-Adenosylhomocysteine/chemical synthesis , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , S-Adenosylhomocysteine/chemistry , S-Adenosylhomocysteine/pharmacology , Structure-Activity RelationshipABSTRACT
The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
Subject(s)
Benzamides/pharmacology , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Pyrimidines/pharmacology , Administration, Oral , Animals , Benzamides/administration & dosage , Benzamides/chemistry , Dogs , Drug Screening Assays, Antitumor , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Humans , Male , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases is described. The compounds demonstrated potency with IC(50) values in the low nanomolar range in vitro while the lead compound also showed in vivo activity against various human tumor xenograft models in mice. Further exploration of this class of compounds is underway.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Division/drug effects , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Humans , Mice , Models, Chemical , Protein Kinase Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Structure-Activity Relationship , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Inhibition of histone deacetylases (HDAC) is emerging as a new strategy in human cancer therapy. The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides is presented herein. From the different series bearing a six-membered heteroaromatic ring studied, the s-triazine series showed the best HDAC1 enzyme and in vitro anti-proliferative activities with IC(50) values below micromolar range. Some of these compounds can also significantly reduce tumor growth in human tumor xenograft models in mice.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Pyrimidines/pharmacology , Triazines/chemical synthesis , Triazines/pharmacology , Animals , Antineoplastic Agents/chemistry , Benzamides/chemistry , Disease Models, Animal , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Mice , Structure-Activity Relationship , Triazines/chemistryABSTRACT
A variety of N-(2-amino-phenyl)-4-(heteroarylmethyl)-benzamides were designed and synthesized. These compounds were shown to inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induced hyperacetylation of histones, induced the expression of the tumor suppressor protein p21(WAF1/Cip1), and inhibited cellular proliferation. Certain compounds of this class also showed in vivo activity in various human tumor xenograft models in mice.
Subject(s)
Benzamides/chemistry , Benzamides/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Amination , Animals , Binding Sites , Cell Line , Histone Deacetylases/chemistry , Histone Deacetylases/metabolism , Humans , Methylation , Mice , Models, Molecular , Molecular Structure , Niacin/pharmacology , Structure-Activity Relationship , Urea/chemistry , Vasodilation/drug effects , ortho-Aminobenzoates/chemistryABSTRACT
A variety of omega-substituted alkanoic acid (2-amino-phenyl)-amides were designed and synthesized. These compounds were shown to inhibit recombinant human histone deacetylases (HDACs) with IC(50) values in the low micromolar range and induce hyperacetylation of histones in whole cells. They induced expression of p21WAF1/Cip1 and caused cell-cycle arrest in human cancer cells. Compounds in this class showed efficacy in human tumor xenograft models.
Subject(s)
Amides/chemistry , Amides/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Cell Cycle/drug effects , Cell Cycle/physiology , Cell Line, Tumor , Histone Deacetylases/metabolism , HumansABSTRACT
A series of new, structurally simple trichostatin A (TSA)-like straight chain hydroxamates were prepared and evaluated for their ability to inhibit partially purified human histone deacetylase 1 (HDAC-1). Some of these compounds such as 8m, 8n, 12, and 15b exhibited potent HDAC inhibitory activity with low nanomolar IC(50) values, comparable to natural TSA. These compounds induce hyperacetylation of histones in T24 human cancer cells and significantly inhibit proliferation in various human cancer cells. They also induce expression of p21 and cause cell cycle blocks in human cancer cells. In this paper, we describe the synthesis of these new compounds as well as structure-activity relationship results from enzyme inhibition and alterations in cellular function.
