Cachexia affects many different chronically ill patient populations, including those with cancer. It results in loss of body weight, particularly of lean body mass (LBM), and is estimated to be responsible for over 20% of all cancer-related deaths. Currently, available drugs are ineffective, and new therapies are urgently needed. The anorexigenic peptide, α-melanocyte stimulating hormone (α-MSH), is believed to be crucially involved in the normal and pathologic regulation of food intake and it was speculated that blockade of its central physiological target, the melanocortin-4 receptor (MC4R), might provide a promising anti-cachexia treatment strategy. The idea is supported by animal studies with agouti-related protein (AgRP), the endogenous inverse agonist at the MC4 receptor, which was found to affect two hallmark features of cachexia: to increase food intake and to reduce energy expenditure.
In 1998, it was reported that MC4R mutations were associated with inherited human obesity. MC4R mutations have a prevalence of 1-2.5% in people with body mass indexes greater than 30, making it the most commonly known genetic defect predisposing people to obesity.
Researchers at Santhera Pharmaceuticals have now published results with orally available MC4R antagonists in an animal model of tumour-induced cachexia. Once daily oral administration of both compounds SNT207858 and SNT207707, starting the day after tumour implantation, significantly reduced the tumour induced weight loss. SNT207707 binds to the MC4 receptor with an affinity of 8 nM and shows a more than 200-fold selectivity vs. MC3 and MC5. SNT207858 is a 22 nM MC4 antagonist with a 170-fold selectivity vs. MC3 and a 40-fold selectivity versus MC5.
Full details of the study are published in the journal PLoS One.