ABSTRACT
The design and enzyme activities of a novel class of imidazo[2,1-b]thiazoles is presented.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Thiazoles/pharmacology , Models, Molecular , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
Emerging clinical and pre-clinical data indicate that both insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor (EGF) family of receptor tyrosine kinases (RTKs) exhibit significant cross-talk in human cancers. Therefore, a small molecule that successfully inhibits the signaling of both classes of oncogenic kinases might provide an attractive agent for chemotherapeutic use. Herein, we disclose the structure activity relationships that led to the synthesis and biological characterization of 14, a novel small molecule inhibitor of both IGF-IR and members of the epidermal growth factor family of RTKs.
Subject(s)
Antineoplastic Agents/chemical synthesis , Chemistry, Pharmaceutical/methods , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Somatomedin/antagonists & inhibitors , Receptors, Somatomedin/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Dimerization , Drug Design , Humans , Lung/metabolism , Models, Chemical , Neoplasms/metabolism , Phosphorylation , Pyrimidines/chemistry , Receptor Protein-Tyrosine Kinases/chemistry , Signal TransductionABSTRACT
The insulin-like growth factor-1 receptor (IGF-1R) and ErbB family of receptors are receptor tyrosine kinases that play important roles in cancer. Lack of response and resistance to therapies targeting ErbB receptors occur and are often associated with activation of the IGF-1R pathway. Combinations of agents that inhibit IGF-1R and ErbB receptors have been shown to synergistically block cancer cell proliferation and xenograft tumor growth. To determine the mechanism by which targeting both IGF-1R and ErbB receptors causes synergistic effects on cell growth and survival, we investigated the effects of combinations of selective IGF-1R and ErbB kinase inhibitors on proliferative and apoptotic signaling. We identified A431 squamous cell carcinoma cells as most sensitive to combinations of ErbB and IGF-1R inhibitors. The inhibitor combinations resulted in not only blockade of A431 cell proliferation, but also induced apoptosis, which was not seen with either agent alone. Upon examining phosphorylation states and expression levels of proteins in the IGF-1R and ErbB signaling pathways, we found a correlation between the ability of combinations to inhibit proliferation and to decrease levels of phosphorylated Akt and cyclin D1. In addition, the massive cell death induced by combined IGF-1R/ErbB inhibition was associated with Mcl-1 reduction and Bax activation. Thus, targeting both IGF-1R and ErbB receptors simultaneously results in cell cycle arrest and apoptosis through combined effects on Akt, cyclin D1, and Bax activation.
Subject(s)
Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Neoplasms/drug therapy , Oncogene Proteins v-erbB/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Animals , Cell Death/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Cyclin D , Cyclins/metabolism , Drug Resistance, Neoplasm/drug effects , Humans , Myeloid Cell Leukemia Sequence 1 Protein , Neoplasm Transplantation , Neoplasms/enzymology , Oncogene Proteins v-erbB/metabolism , Phosphorylation/drug effects , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Receptor, IGF Type 1/metabolism , Signal Transduction/drug effects , Transplantation, Heterologous , bcl-2-Associated X Protein/metabolismABSTRACT
Methionine aminopeptidase-2 (MetAP2) is a novel target for cancer therapy. As part of an effort to discover orally active reversible inhibitors of MetAP2, a series of anthranilic acid sulfonamides with micromolar affinities for human MetAP2 were identified using affinity selection by mass spectrometry (ASMS) screening. These micromolar hits were rapidly improved to nanomolar leads on the basis of insights from protein crystallography; however, the compounds displayed extensive binding to human serum albumin and had limited activity in cellular assays. Modifications based on structural information on the binding of lead compounds to both MetAP2 and domain III of albumin allowed the identification of compounds with significant improvements in both parameters, which showed good cellular activity in both proliferation and methionine processing assays.
Subject(s)
Aminopeptidases/chemistry , Antineoplastic Agents/chemical synthesis , Metalloendopeptidases/chemistry , Serum Albumin/chemistry , Sulfonamides/chemical synthesis , ortho-Aminobenzoates/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , In Vitro Techniques , Mass Spectrometry , Methionine/metabolism , Models, Molecular , Protein Binding , Protein Conformation , Protein Structure, Tertiary , Rats , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/pharmacologyABSTRACT
We have screened molecules for inhibition of MetAP2 as a novel approach toward antiangiogenesis and anticancer therapy using affinity selection/mass spectrometry (ASMS) employing MetAP2 loaded with Mn(2+) as the active site metal. After a series of anthranilic acid sulfonamides with micromolar affinities was identified, chemistry efforts were initiated. The micromolar hits were quickly improved to potent nanomolar inhibitors by chemical modifications guided by insights from X-ray crystallography.
