UCLA

Ghrelin O-acyltransferase (GOAT) is a membrane bound O-acyltransferase (MBOAT) that was recently discovered in 2008. GOAT functions to catalyze the octanoylation of ghrelin, a 28-residue peptide hormone with implications in various metabolic pathways. In its active form, ghrelin plays a role in processes such as glucose homeostasis, insulin secretion and feeding behavior. The ghrelin/GOAT system is unique in that ghrelin is the only known octanoylated hormone and GOAT is the only enzyme known to perform this octanoylation. Thus, the ghrelin/GOAT pathway has high selectivity and specificity. For years, as described in Chapter 1, the MBOAT family of enzymes have been targeted for various therapeutic treatments. We have envisioned that targeting GOAT to disrupt the ghrelin signaling pathway could offer a treatment pathway for metabolic diseases such as obesity and type II diabetes resultant from obesity. Additionally, it is thought that targeting of GOAT could have beneficial implications in treatment of Prader-Willi syndrome, a condition that often leads to the inability for patients to suppress hunger. Chapter 2 discusses the discovery of ghrelin and GOAT. In addition to the specificity afforded by the ghrelin/GOAT system, ghrelin and GOAT are both primarily produced in the stomach and thus inhibitors of GOAT would not need to penetrate the blood brain barrier and could thus mitigate potential toxicities associated with action of the CNS. Chapter 3 describes our efforts toward the development of small molecule peptidomimetic inhibitors of GOAT. Starting from a pyrrolidine-containing lead inhibitor described and developed by former lab member Dr. Ryan Hollibaugh, we detail the efforts toward development of a compound displaying superior in vitro, cellular, and in vivo activity. Compound development led to the discovery of the most potent inhibitor in vitro, the discovery of compounds displaying superior cellular activity, and the first known macrocyclic inhibitor of GOAT. In Chapter 4, the development of a small molecule heterocyclic GOAT inhibitor is described. Inspired by several pharmaceutical companies that began working on GOAT, we developed a small molecule heterocyclic inhibitor that is more “drug-like”. This work led to the discovery of an inhibitor displaying excellent in vitro, cellular, and in vivo efficacy. Compounds of this class provide a foundation for further medicinal chemistry efforts to fine tune the properties for the therapeutic potential of GOAT inhibition.