In This Issue pubs.acs.org/acsmedchemlett
■
DEVELOPMENT OF PRODRUGS OF A BUTYROPHILIN LIGAND Butyrophilins (BTNs), previously known to be important in lactation and milk production, may also be involved in other essential functions, such as the human immune response to pathogens and cancers. BTNs are stimulated by organophosphorus compounds, which lead to Vγ9 Vδ2 T cell proliferation. Researching butyrophilin ligands may advance our understanding of the anticancer properties of these cells; however, the development of effective therapeutics has been hampered in part by the lack of potent butyrophilin-ligand prodrugs that bind to the signaling protein bytyrophilin 3A1 (BTN3A1). In this month’s Featured Letter, Foust et al. (DOI: 10.1021/ acsmedchemlett.7b00245) disclose the discovery of aryl phosphonate derivatives as potent stimulants for Vγ9 Vδ2 T cell proliferation. The prodrugs exhibited rapid cellular internalization, which subsequently led to excellent gain in cellular activity. The team prepared a small set of phosphonate derivatives and identified lead compound 8b, a mixed ester containing one pivaloylmethyl substituent and one 1-naphtyl ester, which effectively stimulated T cell proliferation in the picomolar range. In addition, the phosphonate prodrugs exhibited improved metabolic stability and acceptable cellular permeability. This report is a promising start to the development of effective therapeutics, which may shed light on how the human immune system responds to cancers and pathogens.
■
A NOVEL DEVELOPMENT CANDIDATE FOR TYPE 2 DIABETES Type 2 diabetes is a life-long (chronic) illness and the most common form of diabetes. Studies indicate that type 2 diabetes is on the rise worldwide. The Gq-coupled GPCR that is associated with type 2 diabetes is GPR120, which is activated by long-chain fatty acids. Upon activation, it can facilitate events such as insulin sensitization and anti-inflammation, among others. As a result, GPR120 has become a sought-after target for the treatment of diseases such as type 2 diabetes and obesity. Herein, Zhang et al. (DOI: 10.1021/acsmedchemlett.7b00233) disclose a series of isothiazole-based phenylpropanoic acids as GPR120 agonists. The team performed extensive structural− activity relationship studies and obtained a lead compound, 4x. Compound 4x is a potent GPR120 agonist, which lowered the plasma glucose levels in in vivo studies in mice. In addition, 4x exhibited favorable pharmaceutical properties, oral bioavailability, and a clean safety profile. Therefore, this compound has the potential for further development into an antidiabetic drug.
■
DISCOVERY OF A HEDGEHOG SIGNALING INHIBITOR The Hedgehog (Hh) pathway is an essential molecular signaling pathway involved in various key processes, including cell control growth and proliferation. Of particular interest is the Hh pathway that directs the development of multiple tissues during embryonic development and contributes to tissue homeostasis in adults. Present therapeutics that control the misregulation of Hh signal in cancers of the breast, skin, ovaries, brain, and prostate have developed resistance, and urgent new therapeutics are highly needed. In their letter, Gräßle et al. (DOI: 10.1021/acsmedchemlett.7b00100) report on the novel use of 2-mercaptobenzoimidazoles as inhibitors of Hh signaling, which exhibited low micromolar range activity. The team screened a library of 940 compounds and found the S-alkylated 2-mercaptobenzoimidazoles as a new class of compounds, which regulate the Hh signaling pathway. The inhibitory activities of the most promising compounds were subsequently assayed, which validated their Hh inhibitory activity. These compounds serve as a very promising start for the development of novel Hh inhibitors. © 2017 American Chemical Society
Published: September 14, 2017 892
DOI: 10.1021/acsmedchemlett.7b00348 ACS Med. Chem. Lett. 2017, 8, 892−892
