Targeting the adrenomedullin-2 receptor for the discovery and development of novel anti-cancer agents

Introduction Adrenomedullin (AM) is a peptide responsible for many physiological processes including vascular health and hormone regulation. Dysregulation of AM signaling can stimulate cancers by promoting proliferation, angiogenesis and metastasis. Two AM receptors contribute to tumor progression in different ways. Adrenomedullin-1 receptor (AM(1)R) regulates blood pressure and blocking AM signaling via AM(1)R would be clinically unacceptable. Therefore, antagonizing adrenomedullin-2 receptor (AM(2)R) presents as an avenue for anti-cancer drug development. Areas covered We review the literature to highlight AM's role in cancer as well as delineating the specific roles AM(1)R and AM(2)R mediate in the development of a pro-tumoral microenvironment. We highlight the importance of exploring the residue differences between the receptors that led to the development of first-in-class selective AM(2)R small molecule antagonists. We also summarize the current approaches targeting AM and its receptors, their anti-tumor effects and their limitations. Expert opinion As tool compounds, AM(2)R antagonists will allow the dissection of the functions of CGRPR (calcitonin gene-related peptide receptor), AM(1)R and AM(2)R, and has considerable potential as a first-in-class oncology therapy. Furthermore, the lack of detectable side effects and good drug-like pharmacokinetic properties of these AM(2)R antagonists support the promise of this class of compounds as potential anti-cancer therapeutics.

Automated summary

As an introduction, adrenomedullin (AM) is a peptide responsible for physiological processes and dysregulation of AM signaling can stimulate cancers. Two AM receptors play different roles in tumor progression. The importance of exploring the differences between the receptors and the development of selective AM(2)R antagonists is highlighted. The current approaches, anti-tumor effects, and limitations of targeting AM and its receptors are summarized.