Dual Action Calcium-Sensing Receptor Modulator Unmasks Novel Mode-Switching Mechanism
Karen J Gregory, Irina Kufareva, Andrew N Keller, Elham Khajehali, Hee-Chang Mun, Mahvash A Goolam, Rebecca S Mason, Ben Capuano, Arthur D Conigrave, Arthur Christopoulos, Katie Leach
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE | AMER CHEMICAL SOC | Published : 2018
Negative allosteric modulators (NAMs) of the human calcium-sensing receptor (CaSR) have previously failed to show efficacy in human osteoporosis clinical trials, but there is now significant interest in repurposing these drugs for hypocalcemic disorders and inflammatory lung diseases. However, little is known about how CaSR NAMs inhibit the response to endogenous activators. An improved understanding of CaSR negative allosteric modulation may afford the opportunity to develop therapeutically superior CaSR-targeting drugs. In an attempt to elucidate the mechanistic and structural basis of allosteric modulation mediated by the previously reported NAM, calhex231, we herein demonstrate that calh..View full abstract
Awarded by National Health and Medical Research Council of Australia (NHMRC)
Awarded by National Institutes of Health National Institute of General Medical Sciences
Awarded by National Institutes of Health National Institute of Allergy and Infectious Diseases
Thanks go to Alisha Panwar and Aaron P Townley for their contribution to experiments in HEK293 cells. This work was supported by National Health and Medical Research Council of Australia (NHMRC) Project Grant APP1085143, and by and the National Institutes of Health National Institute of General Medical Sciences and National Institute of Allergy and Infectious Diseases Grants GM117424 and AI118985, respectively. K.L. and K.J.G. are Australian Research Council Future Fellows. A.C. is a Senior Principal Research Fellow of the NHMRC.