S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization.

Quinone reductase 2 (QR2, E.C. 1.10.5.1) is an enzyme with a feature that has attracted attention for several decades: in standard conditions, instead of recognizing NAD(P)H as an electron donor, it recognizes putative metabolites of NADH, such as N-methyl- and N-ribosyl-dihydronicotinamide. QR2 has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration. In molecular and cellular pharmacology, understanding physiopathological associations can be difficult because of a lack of specific and powerful tools. Here, we present a thorough description of the potent, nanomolar inhibitor [2-(2-methoxy-5H-1,4b,9-triaza(indeno[2,1-a]inden-10-yl)ethyl]-2-furamide (S29434 or NMDPEF; IC50 = 5-16 nM) of QR2 at different organizational levels. We provide full detailed syntheses, describe its cocrystallization with and behavior at QR2 on a millisecond timeline, show that it penetrates cell membranes and inhibits QR2-mediated reactive oxygen species (ROS) production within the 100 nM range, and describe its actions in several in vivo models and lack of actions in various ROS-producing systems. The inhibitor is fairly stable in vivo, penetrates cells, specifically inhibits QR2, and shows activities that suggest a key role for this enzyme in different pathologic conditions, including neurodegenerative diseases.

Recent updates on Wnt signaling modulators: a patent review (2014-2020).

Introduction: Wnt signaling is a signal transduction pathway that plays a vital role in embryonic development and normal tissue preservation. Dysfunction of it gives rise to various diseases like cancer, Alzheimer's, metabolic and skeletal disorders, kidney and liver disease, etc. Thus, targeting Wnt pathway can be a potential approach to design and develop novel therapeutic classes.Areas covered: Authors provided an overview of Wnt modulators from 2014 to 2020. Different heterocyclic scaffolds and their pharmacology from a total of 104 PCT applications have been summarized.Expert opinion: The scientific community is working extensively to bring first in the class molecule to the market which targets Wnt pathway. Lorecivivint, Wnt inhibitor, for the treatment of knee Osteoarthritis and SM-04554, Wnt activator, for the treatment of androgenetic alopecia are currently under Phase III. Other molecules, LGK-974, RXC-004, ETC-159, CGX-1321, PRI-724, CWP-232291 and BC-2059 are also under different stages of clinical development for the treatment of cancer. Antibody based Wnt modulator, OTSA101-DTPA-90Y is currently under Phase I for the treatment of Relapsed or Refractory Synovial Sarcoma while OMP-18R5 is under Phase I for Metastatic Breast Cancer.  Ongoing preclinical/clinical trials will define the role of the Wnt pathway in different therapeutic areas and open new opportunities.