ABSTRACT
LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRß, FLT-3, Tie-2 and members of the Eph family of receptors. With activities against both Tie2 and Eph receptors, LY2457546 possesses an activity profile that distinguishes it from multikinase inhibitors. When compared head to head with sunitinib, LY2457546 was more potent for inhibition of endothelial tube formation in an in vitro angiogenesis co-culture model with an intermittent treatment design. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor model in both once and twice daily continuous dosing schedules and in mouse human tumor xenograft models of lung, colon, and prostate origin. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The observed efficacy that was displayed by LY2457546 in the AML FLT3-ITD mutant tumor model was superior to sunitinib when both were evaluated using equivalent doses normalized to in vivo inhibition of pKDR in mouse lung. LY2457546 was well tolerated in non-clinical toxicology studies conducted in rats and dogs. The majority of the toxicities observed were similar to those observed with other multi-targeted anti-angiogenic kinase inhibitors (MAKs) and included bone marrow hypocellularity, hair and skin depigmentation, cartilage dysplasia and lymphoid organ degeneration and necrosis. Thus, the unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non-clinical safety profile justify the advancement of LY2457546 into clinical testing.
Subject(s)
Acetanilides/therapeutic use , Angiogenesis Inhibitors/therapeutic use , Neoplasms, Experimental/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyridines/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Acetanilides/chemical synthesis , Acetanilides/pharmacology , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/pharmacology , Animals , CHO Cells , Cell Line, Tumor , Cricetinae , Cricetulus , Dogs , Female , Human Umbilical Vein Endothelial Cells , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Mice , Mice, Nude , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Xenograft Model Antitumor Assays , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.
Subject(s)
Antineoplastic Agents/chemical synthesis , Sulfonamides/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Division/drug effects , Cell Line , Drug Screening Assays, Antitumor , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Female , Half-Life , Humans , In Vitro Techniques , Mice , Mice, Nude , Quantitative Structure-Activity Relationship , Rats , Rats, Inbred F344 , Sulfonamides/chemistry , Sulfonamides/pharmacology , Transplantation, Heterologous , Umbilical Veins/cytology , Vascular Endothelial Growth Factor A/pharmacology , Vascular Endothelial Growth Factor A/physiologyABSTRACT
The synthesis of novel aza-1,7-annulated indoles was achieved and these were converted to indolocarbazoles that proved to be potent kinase inhibitors. These compounds were also evaluated in a human colon carcinoma cell line and proved to be good antiproliferative agents.
Subject(s)
Aza Compounds/chemical synthesis , CDC2-CDC28 Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Indoles/chemical synthesis , Aza Compounds/pharmacology , Binding Sites , CDC2-CDC28 Kinases/chemistry , Cell Cycle/drug effects , Cyclin-Dependent Kinase 2 , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
The synthesis of a novel series of 1,7-annulated indolocarbazoles 2 and 16 is described. These compounds were found to be potent cyclin dependent kinase inhibitors with good antiproliferative activity against two human carcinoma cell lines. These inhibitors also arrested tumor cells at the G1 phase and inhibited pRb phosphorylation.
Subject(s)
Cyclin-Dependent Kinases/antagonists & inhibitors , Indoles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cyclin-Dependent Kinases/metabolism , Growth Inhibitors/chemical synthesis , Growth Inhibitors/pharmacology , Humans , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacologyABSTRACT
The synthesis and kinase inhibitory activity of a series of novel 1,7-annulated indolocarbazoles 6 and 16 is described. These compounds exhibited potent inhibitory activity against cyclin-dependent kinase 4 and good antiproliferative activity in a human colon carcinoma cell line.
Subject(s)
Carbazoles/chemistry , Cyclin-Dependent Kinases/antagonists & inhibitors , Indoles/chemistry , Protein Kinase Inhibitors/chemistry , Carbazoles/pharmacology , Cyclin D1/antagonists & inhibitors , Cyclin D1/metabolism , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinases/metabolism , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolismABSTRACT
Bone metastasis from primary tumors is a clinically important complication of neoplastic progression. The role of parathyroid hormone-related protein (PTHrP) and transforming growth factor (TGF)-beta1 in this process has been clearly established. The current study describes an in vivo model of 13762 rat mammary carcinoma tumor cell-induced osteolysis in which PTHrP and TGF-beta1 expression is observed. Exposure of in vitro-cultured 13762 cells to doxorubicin, cis-platinum, carboplatin, methotrexate, 5-fluorouracil, paclitaxel, alendronate, risedronate, or pamidronate for 72 h resulted in varying effects on cell proliferation (IC(50) values of 0.005, 0.4, 1.9, >40, 17.9, 0.003, >40, >40, and 33.6 micro M, respectively). Tumor cells were implanted into the intramedullary space of the proximal tibia of rats, and the time course of tumor progression was evaluated using radiographic and microcomputed tomography scanning techniques. Trabecular bone mineral density, cortical bone mineral density, and whole bone mineral density were measured (in mg/cm(3)). In untreated animals, radiographic evidence of osteolysis was evident 7 days after implantation. Trabecular bone mineral density and whole bone mineral density were significantly decreased by 21 days after implantation (48% and 26%, respectively). Bisphosphonates showed broad protective activity against tumor-driven osteolysis, Immunohistochemical evaluation of s.c. and intratibially implanted cells demonstrated the expression of PTHrP and TGF-beta1. The results of this study demonstrate the ability of 13762 rat mammary carcinoma cells to elicit a measurable osteolysis and that bisphosphonates inhibit the tumor-induced bone resorption in this model.
Subject(s)
Bone Resorption/prevention & control , Diphosphonates/therapeutic use , Mammary Neoplasms, Experimental/drug therapy , Animals , Antineoplastic Agents/toxicity , Bone Resorption/etiology , Cell Division/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Disease Progression , Female , Humans , Mammary Neoplasms, Experimental/complications , Neoplasm Metastasis , Osteolysis/etiology , Osteolysis/prevention & control , Parathyroid Hormone-Related Protein/analysis , Parathyroid Hormone-Related Protein/genetics , Rats , Rats, Inbred F344 , Transforming Growth Factor beta/analysis , Transforming Growth Factor beta/geneticsABSTRACT
The synthesis and CDK inhibitory properties of a series of indolo[6,7-a]pyrrolo[3,4-c]carbazoles is reported. In addition to their potent CDK activity, the compounds display antiproliferative activity against two human cancer cell lines. These inhibitors also effect strong G1 arrest in these cell lines and inhibit Rb phosphorylation at Ser780 consistent with inhibition of cyclin D1/CDK4.