Growth hormone receptor antagonists: discovery, development, and use in patients with acromegaly.
An understanding of the events that occur during GH receptor (GHR) signaling has facilitated the development of a GHR antagonist (pegvisomant) for use in humans. This molecule has been designed to compete with native GH for the GHR and to prevent its proper or functional dimerization-a process that is critical for GH signal transduction and IGF-I synthesis and secretion. Clinical trials in patients with acromegaly show GHR blockade to be an exciting new mode of therapy for this condition, and pegvisomant may have a therapeutic role in diseases, such as diabetes and malignancy, in which abnormalities of the GH/IGF-I axis have been observed. This review charts the discovery and development of GHR antagonists and details the experience gained in patients with acromegaly.
Kopchick
J J
JJ
Edison Biotechnology Institute, Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, USA.
Parkinson
C
C
Stevens
E C
EC
Trainer
P J
PJ
D000172:Acromegaly / Q000188:drug therapy*; D000818:Animals; D002986:Clinical Trials as Topic; D015195:Drug Design; D019382:Human Growth Hormone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000235:genetics / Q000502:physiology / Q000627:therapeutic use; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011986:Receptors, Somatotropin / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship
D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; C406545:pegvisomant