Advances in calcium-sensing receptor modulation: biased signaling and therapeutic potential

In a recent study published in Science, Liu and colleagues used computational ultra-large library docking to discover new chemotypes acting as positive allosteric modulators (PAM) of the Calcium-Sensing Receptor (CaSR),¹ which bind the receptor with very high affinity and shows evidence of biased signaling, i.e. the preferential activation of one signaling pathway over others, compared to the receptor’s natural ligands. Importantly, the in vivo test of one substance (‘54159) did not induce hypocalcemia, which is an advantage over FDA-approved calcimimetics, which are limited in clinical practice due to their potential to disrupt calcium homeostasis and cause hypocalcemia.