In This Issue pubs.acs.org/acsmedchemlett
■
NOVEL HUMAN TYROSINASE INHIBITORS Tyrosinases are metalloenzymes involved in the formation of melanin, a process called melanogenesis. Deregulation of tyrosinases is linked to various skin disorders, including hyperpigmentation, melanoma resistance, and skin lesions. This demonstrates the need for effective enzyme inhibitors, yet most reported tyrosinase inhibitors have only been assessed on the mushroom enzyme, which lacks homology to the human version. In this issue, Haudecoeur et al. (DOI: 10.1021/acsmedchemlett.6b00369) investigated a panel of compounds using both isolated human tyrosinase and a human melanoma cellular model assay. The authors synthesized aurone derivatives featuring a nonoxidizable 2-hydroxypyridin-N-oxide (HOPNO) moiety and subsequently evaluated their efficacy as inhibitors of human tyrosinase. They identified HOPNO-embedded 6-hydrooxyaurone as the most active human tyrosinase inhibitor to date. These compounds could prove valuable in understanding the role of tyrosinases in human pathologies, such as melanoma.
lead to the future development of prodrugs to facilitate cellular uptake.
■
SEVEN-MEMBERED PROSTACYCLIN ANALOGUES AS PROSTAGLANDIN FP AND EP3 DUAL AGONISTS Glaucoma is a chronic eye condition characterized by damage to the optic nerve as a result of elevated eye pressure. Primary treatment involves administration of agents that control intraocular pressure by acting on the prostaglandin FP receptor. It was recently discovered that prostaglandin analogues also target the EP3 receptor. Therefore, superior treatment results for glaucoma could be achieved through simultaneous activation of both the FP and EP3 receptors. In this issue, Maruyama et al. (DOI: 10.1021/acsmedchemlett.6b00415) discovered highly selective FP and EP3 dual agonists containing a novel seven-membered prostacyclin scaffold. Starting from a nonselective agonist for prostaglandin receptors, the authors replaced the core structure with an octahydro-2H-cyclopenta[b]oxepine scaffold and obtained a dual agonist with selectivity toward both the FP and EP3 receptors. This work could lead to the development of novel antiglaucoma agents.
■
COVALENT GUANOSINE MIMETIC INHIBITORS OF G12C KRAS Ras proteins belong to a large family of GTPase enzymes that are prone to mutations in malignant tumors. Inhibition of KRAS in tumor models leads to tumor regression, thus making it an attractive therapeutic target for the treatment of cancer. The most common RAS mutation found in nonsmall cell lung cancer is KRAS G12C. The previously identified GDP-mimetic inhibitor SML-8-73-1 demonstrated high selectivity against KRAS G12C, but the presence of charged phosphates presents hydrolytic instability and prevents efficient cellular uptake. In this issue, Gray et al. (DOI: 10.1021/acsmedchemlett.6b00373) synthesized analogues of SML-8-73-1 and performed biochemical characterization of these. Their work led to the identification of several difluoromethylene bisphosphonate analogues with activity against G12C KRAS. Even though these compounds showed reduced efficiency as covalent G12C KRAS inhibitors relative to the original compound SML-8-73-1, they exhibited hydrolytic stability due to the lack of the diphosphate moiety present in SML-8-73-1. This group of molecules could © 2017 American Chemical Society
Published: January 12, 2017 3
DOI: 10.1021/acsmedchemlett.6b00511 ACS Med. Chem. Lett. 2017, 8, 3−3
