A new drug which could improve life expectancy and quality for patients with hard-to-treat cancers, such as pancreatic cancer and relapsed breast cancer, has been developed by scientists at the University of Sheffield.
The researchers have founded the spin-out company Modulus Oncology, along with a team of experienced biotech entrepreneurs, to fast-track the drug into clinical testing within two years.
The Sheffield team made the discovery after examining the hormone adrenomedullin, which controls blood pressure and other vital body processes, but also stimulates the growth and spread of cancer.
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 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.
In the journal ACS Pharmacology & Translational Science, the team describes the design, synthesis and characterisation of potent small-molecule adrenomedullin-2 receptor antagonists with 1000-fold selectivity over the adrenomedullin-1 receptor, however, 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 tumour growth and extend life in a mouse model of pancreatic cancer.
Taken together, the 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.
