The
hormone adrenomedullin has both physiological and pathological
roles in biology. As a potent vasodilator, adrenomedullin is critically
important in the regulation of blood pressure, but it also has several
roles in disease, of which its actions in cancer are becoming recognized
to have clinical importance. Reduced circulating adrenomedullin causes
increased blood pressure but also reduces tumor progression, so drugs
blocking all effects of adrenomedullin would be unacceptable clinically.
However, there are two distinct receptors for adrenomedullin, each
comprising the same G protein-coupled receptor (GPCR), the calcitonin
receptor-like receptor (CLR), together with a different accessory
protein known as a receptor activity-modifying protein (RAMP). The
CLR with RAMP2 forms an adrenomedullin-1 receptor, and the CLR with
RAMP3 forms an adrenomedullin-2 receptor. Recent research suggests
that a selective blockade of adrenomedullin-2 receptors would be therapeutically
valuable. Here we describe the design, synthesis, and characterization
of potent small-molecule adrenomedullin-2 receptor antagonists with
1000-fold selectivity over the adrenomedullin-1 receptor, although
retaining activity against the CGRP receptor. These molecules have
clear effects on markers of pancreatic cancer progression in vitro, drug-like pharmacokinetic properties, and inhibit
xenograft tumor growth and extend life in a mouse model of pancreatic
cancer. Taken together, our data support the promise of a new class
of anticancer therapeutics as well as improved understanding of the
pharmacology of the adrenomedullin receptors and other GPCR/RAMP heteromers.