ABSTRACT
Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. We developed the novel TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a potent DNA topoisomerase I inhibitor (DXd), and evaluated its antitumor activity and safety profiles in preclinical models.The pharmacologic activity and mechanism of action of Dato-DXd were investigated in several human cancer cell lines and xenograft mouse models including patient-derived xenograft (PDX) models. Safety profiles were also assessed in rats and cynomolgus monkeys.Dato-DXd bound specifically to TROP2 and was internalized into tumor cells followed by intracellular trafficking to lysosome and DXd release, which induced DNA damage and apoptosis in TROP2-expressing tumor cells in vitro. Dato-DXd exhibited in vivo antitumor activity with DNA damage induced by the accumulated DXd in TROP2-expressing xenograft tumors, but neither isotype control IgG-ADC nor anti-TROP2 antibody had this effect. Dato-DXd also showed potent antitumor activity with tumor regression in several TROP2-expressing xenograft tumors including NSCLC PDX models. Safety profiles of Dato-DXd in rats and cynomolgus monkeys were acceptable.Dato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors by efficient payload delivery into tumors and acceptable safety profiles in preclinical models. These results suggest Dato-DXd could be a valuable treatment option for patients with TROP2-expressing tumors in the clinical setting.
Subject(s)
Antineoplastic Agents/therapeutic use , Drug Delivery Systems/methods , Immunoconjugates/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Humans , Immunoconjugates/pharmacology , Macaca fascicularis , Male , Mice , Mice, Nude , RatsABSTRACT
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure-activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.
Subject(s)
Aminopyridines/pharmacology , Anemia/drug therapy , Hepcidins/antagonists & inhibitors , Quinazolines/pharmacology , Administration, Oral , Aminopyridines/administration & dosage , Aminopyridines/chemical synthesis , Aminopyridines/pharmacokinetics , Anemia/etiology , Animals , Binding Sites , Cell Line, Tumor , Drug Design , Hepcidins/blood , Hepcidins/chemistry , Humans , Inflammation/chemically induced , Inflammation/complications , Interleukin-6/metabolism , Iron/metabolism , Male , Mice, Inbred C57BL , Molecular Structure , Quinazolines/administration & dosage , Quinazolines/chemical synthesis , Quinazolines/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis, and its inhibition could be a favorable strategy for treating anemia of chronic disease (ACD). Here, we report the design, synthesis and structure-activity relationships (SAR) of a series of 4,6-disubstituted indazole compounds as hepcidin production inhibitors. The optimization study of multi-kinase inhibitor 1 led to the design of a potent and bioavailable hepcidin production inhibitor, 32 (DS28120313), which showed serum hepcidin-lowering effects in an interleukin-6-induced acute inflammatory mouse model.
Subject(s)
Acute Lung Injury/drug therapy , Drug Discovery , Hepcidins/antagonists & inhibitors , Indazoles/pharmacology , Inflammation/drug therapy , Pyrazoles/pharmacology , Acute Lung Injury/chemically induced , Administration, Oral , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Hep G2 Cells , Hepcidins/biosynthesis , Humans , Indazoles/administration & dosage , Indazoles/chemistry , Inflammation/chemically induced , Interleukin-6 , Mice , Molecular Structure , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of benzisoxazole compounds as orally active hepcidin production inhibitors. The optimization study of multi kinase inhibitor 1 led to a potent and bioavailable hepcidin production inhibitor 38 (DS79182026), which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.
Subject(s)
Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Hepcidins/antagonists & inhibitors , Administration, Oral , Animals , Benzoxazoles/administration & dosage , Benzoxazoles/pharmacokinetics , Carbamates/administration & dosage , Carbamates/pharmacokinetics , Gene Expression Regulation/drug effects , Half-Life , Hepcidins/genetics , Hepcidins/metabolism , Inflammation/chemically induced , Inflammation/drug therapy , Inhibitory Concentration 50 , Interleukin-6 , Maleates/administration & dosage , Maleates/chemistry , Maleates/pharmacokinetics , Maleates/pharmacology , Mice , Mice, Inbred C57BL , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Animal , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , RNA, Messenger/metabolism , Structure-Activity RelationshipABSTRACT
Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of indazole compounds as hepcidin production inhibitors. The optimization study of compound 1 led to a potent hepcidin production inhibitor 45, which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.
Subject(s)
Anti-Infective Agents/chemical synthesis , Hepcidins/antagonists & inhibitors , Indazoles/chemistry , Anemia/drug therapy , Anemia/etiology , Animals , Anti-Infective Agents/pharmacokinetics , Anti-Infective Agents/therapeutic use , Chronic Disease , Half-Life , Hepcidins/blood , Hepcidins/metabolism , Indazoles/pharmacokinetics , Indazoles/therapeutic use , Inhibitory Concentration 50 , Interleukin-6/toxicity , Mice , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Structure-Activity RelationshipABSTRACT
We compared the antithrombotic properties of a factor Xa inhibitor (DX-9065a) with those of a thrombin inhibitor (melagatran) in a rat disseminated intravascular coagulation model and a rat venous thrombosis model. Rat disseminated intravascular coagulation and venous thrombosis models were produced by injection of tissue factor and platinum wire placement, respectively. DX-9065a exerted antithrombotic effects dose dependently in both models. Melagatran was also effective in the venous thrombosis model, whereas it showed an aggravation in the disseminated intravascular coagulation model at low but not high doses. In the in vitro study, DX-9065a decreased the C(max) of the thrombin generation curve in plasma irrespective of whether protein C was present or not. However, melagatran increased the C(max) at low concentrations when protein C was present. This increase was not detected in protein C-deficient plasma. These results suggest that, unlike DX-9065a, melagatran in low doses aggravates disseminated intravascular coagulation by increasing thrombin generation, which may be partly due to suppression of negative feedback by activated protein C.
