ABSTRACT
5-Alkenyl or 5-alkynyl-4-anilinopyrimidines were prepared and evaluated for in vitro inhibition of EGFR/Her-2 kinase activity and the growth of tumor cell lines (BT474 and N87). Several of these compounds inhibited the growth of BT474 and N87 at concentrations below 200nM. Structure-activity relationship studies revealed a critical role for the 5-alkynyl moieties. The representative compound 19 exhibited significant antitumor potency in a mouse xenograft model.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Drug Screening Assays, Antitumor/methods , Enzyme Inhibitors/pharmacology , ErbB Receptors/chemistry , Humans , Hydrogen-Ion Concentration , Inhibitory Concentration 50 , Mice , Microsomes, Liver/metabolism , Models, Chemical , Neoplasm Transplantation , Pyrimidines/chemistry , Rats , Receptor, ErbB-2/chemistry , Structure-Activity RelationshipABSTRACT
A structure-activity relationship study of 4-anilinopyrimidines for dual EGFR/Her-2 inhibitor has resulted in the identification of 4-anilino-5-alkenyl or 5-alkynyl-6-methylpyrimidine derivatives that have exhibited effective inhibitory activity against both enzymes. The presence of 5-alkenyl or 5-alkynyl moiety bearing terminal hydrophilic group played important role for inhibition of these enzymes. Selected compounds in the series demonstrated some activity against Her-2 dependent cell line (BT474).
Subject(s)
ErbB Receptors/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Crystallography, X-Ray , Drug Evaluation, Preclinical , ErbB Receptors/chemistry , Humans , Models, Molecular , Structure-Activity RelationshipABSTRACT
OBJECTIVE: The objective of this study was to evaluate the benefits of combination therapy consisting of recombinant human interleukin-2 and sorafenib for survival efficacy and the suppression of metastasis in murine renal cell carcinoma models. METHODS: Lung-metastasized renal cell carcinoma mice were treated with various combinations of recombinant human interleukin-2 and sorafenib. Tumor growth was observed using a bioluminescence imaging system. Next, the nephrectomized renal cell carcinoma mice were administered various combinations of recombinant human interleukin-2 and sorafenib, followed by a lung resection in order to examine lung metastasis by bioluminescence imaging. RESULTS: The increased life-span ratio in mice receiving combination therapy was 1.45, whereas that in mice treated with sorafenib or recombinant human interleukin-2 alone therapy was 1.28 and 1.07, respectively. The concomitant administration of recombinant human interleukin-2 and sorafenib had a metastasis-inhibitory effect, whereas the other treatments failed. CONCLUSIONS: These findings indicate that combination therapy of recombinant human interleukin-2 and sorafenib may offer better outcomes than either monotherapy with recombinant human interleukin-2 or sorafenib with respect to survival benefits and the prevention of pulmonary metastasis in renal cell carcinoma patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzenesulfonates/administration & dosage , Carcinoma, Renal Cell/secondary , Interleukin-2/administration & dosage , Kidney Neoplasms/pathology , Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Pyridines/administration & dosage , Animals , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/surgery , Cell Line, Tumor , Female , Kidney Neoplasms/drug therapy , Kidney Neoplasms/mortality , Kidney Neoplasms/surgery , Lung Neoplasms/mortality , Mice , Mice, Inbred BALB C , Nephrectomy , Niacinamide/analogs & derivatives , Phenylurea Compounds , Recombinant Proteins/administration & dosage , Sorafenib , Survival RateABSTRACT
Monopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diaminopyridine 9 with an IC50 of 37 nM. The X-ray structure of 9 revealed that the Cys604 carbonyl group of the hinge region flips to form a hydrogen bond with the aniline NH group in 9. Further optimization of 9 led to 12 with improved cellular activity, suitable pharmacokinetic profiles, and good in vivo efficacy in the mouse A549 xenograft model. Moreover, 12 displayed excellent selectivity over 95 kinases, indicating the contribution of its unusual flipped-peptide conformation to its selectivity.