pyrrolopyrimidine and Breast-Neoplasms

AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine-derived compound, inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 μmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 μmol/L or less. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363 and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused dose- and time-dependent reduction of PRAS40, GSK3β, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC(50) ~ 0.1 μmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-D-glucose ((18)F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2(+) breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS. AZD5363 is currently in phase I clinical trials.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; Male; Mice; Mice, Nude; Mice, SCID; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Pyrimidines; Pyrroles; Signal Transduction; Xenograft Model Antitumor Assays

A series of novel 2,4-diaminosubstituted pyrrolo[3,2-d]pyrimidines was synthesized together with their corresponding 7-phenyl or 7-isopropyl counterparts.. Among the target derivatives, the 7-substituted analogues exhibited interesting cytotoxic activity against a panel of PI3Kα related human breast cancer cell lines, namely MCF7, T47D, MDA-MB-231 and HCC1954. Selected compounds were tested for potential PI3Kα inhibitory activity as well as for their cytotoxic effect in prostate cancer cell lines (DU145 and PC3).. Derivatives bearing a specific substitution pattern consisting of 7-phenyl as well as a 2-(4- aminocyclohexylamino) moiety (16c, 16f) display kinase inhibitory activity, elucidated on the basis of molecular simulation studies, which revealed their interaction with the DFG motif of the kinase.

Topics: Amination; Antineoplastic Agents; Breast; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Drug Design; Drug Screening Assays, Antitumor; Female; Humans; Male; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Prostate; Prostatic Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Pyrroles

Epidermal growth factor receptor tyrosine kinase inhibitors are useful in treatment of non-small cell lung cancer, and show promise in combination therapy settings. Two novel chiral pyrrolopyrimidines have been baselined towards Erlotinib, Lapatinib and Dasatinib using in vitro cellular studies and ADME profiling. One of these, (S)-2-((6-(4-(hydroxymethyl)-2-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-phenylethan-1-ol, was more active than Erlotinib in lung and breast cancer cell models. The compound also had promising activity towards ovarian cancer cell lines, while low activity was seen towards cells of haematological origin. ADME profiling revealed good solubility, higher metabolic stability than Erlotinib and no inhibitory effect towards the hERG voltage-gated ion channel. Investigation of inhibitory potency towards 6 CYP isoforms generally revealed low inhibitory potency, but in the case of CYP3A4, a substrate dependent inhibition was noted using testosterone as substrate (IC50: 12.5μM). No cellular or gene toxicity was noted for the compounds or products of phase I metabolism. However, permeability studies using Caco-2 cells revealed a high efflux ratio. Further experiments using ABC transporter inhibitors revealed that the pyrrolopyrimidines are actively transported by the breast cancer resistant protein and P-glycoprotein transporters, which might prevent their further development into drugs.

Topics: Antineoplastic Agents; Breast Neoplasms; Caco-2 Cells; Cell Line, Tumor; Cell Proliferation; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; In Vitro Techniques; Lung Neoplasms; Ovarian Neoplasms; Pyrimidines; Pyrroles

Novel pyrrole and pyrrolopyrimidine scaffold-based sulfonamides were designed and synthesized. The carbonic anhydrase (CA) inhibition ability of all derivatives was assessed against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated isoforms hCA IX and XII. Some of these sulfonamides were 6-8 fold more potent than the reference drug acetazolamide (AZA, Ki = 5.7 nM)) against hCA XII showing subnanomolar activity. The in vitro cytotoxicity of these derivatives was evaluated against MCF-7, where some derivatives were more cytotoxic than doxorubicin (IC50 = 8.02 μM) displaying IC50 values between 6.46 and 7.56 μM. Docking of these sulfonamides with CA XII was performed and their binding modes were comparable with that of AZA.

Topics: Antigens, Neoplasm; Antineoplastic Agents; Breast Neoplasms; Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Carbonic Anhydrase IX; Carbonic Anhydrases; Cell Proliferation; Drug Screening Assays, Antitumor; Female; Flow Cytometry; Humans; Models, Molecular; Molecular Structure; Pyrimidines; Pyrroles; Structure-Activity Relationship; Sulfonamides; Tumor Cells, Cultured

Our lead compound for a phosphoinositide 3-kinase (PI3K) inhibitor (1) was metabolically unstable because of rapid glucuronidation of the phenol moiety. Based on structure-activity relationship (SAR) information and a FlexSIS docking simulation score, aminopyrimidine was identified as a bioisostere of phenol. An X-ray structure study revealed a hydrogen bonding pattern of aminopyrimidine derivatives. Finally, aminopyrimidine derivatives 33 showed strong tumor growth inhibition against a KPL-4 breast cancer xenograft model in vivo.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Crystallography, X-Ray; Enzyme Activation; Female; Glucuronic Acid; Humans; Hydrogen Bonding; Inhibitory Concentration 50; Mice; Molecular Structure; Phenols; Phosphoinositide-3 Kinase Inhibitors; Pyrimidines; Pyrroles; Structure-Activity Relationship; Xenograft Model Antitumor Assays

A series of 2,4-disubstituted 6-aryl-7H-pyrrolo[3,2-d]pyrimidin-7-one 5-oxides were synthesized and in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780, HBL-100, HeLa, SW1573, T-47D, and WiDr. The most potent analog induced considerably growth inhibition in the range 0.35-2.0microM. Cell cycle studies in the breast and lung cancer cells revealed arrest in the G(2)/M compartment. The results showed that the title compounds bearing alkylamino or dialkylamino moieties in position 2 of the pyrimidine ring are more active than those bearing hydrogen or methylthio groups.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Oxides; Pyrimidines; Pyrroles