ABSTRACT
GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 µM)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5 g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; >100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; >100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay.
Subject(s)
Drug Discovery , Receptors, G-Protein-Coupled/antagonists & inhibitors , Small Molecule Libraries/chemical synthesis , Administration, Oral , Animals , Inhibitory Concentration 50 , Male , Molecular Structure , Rats , Rats, Wistar , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacologyABSTRACT
Stem cells including cancer stem cells (CSC) divide symmetrically or asymmetrically. Usually symmetric cell division makes two daughter cells of the same fate, either as stem cells or more differentiated progenies; while asymmetric cell division (ACD) produces daughter cells of different fates. In this review, we first provide an overview of ACD, and then discuss more molecular details of ACD using the well-characterized Drosophila neuroblast system as an example. Aiming to explore the connections between cell heterogeneity in cancers and the critical need of ACD for self-renewal and generating cell diversity, we then examine how cell division symmetry control impacts common features associated with CSCs, including niche competition, cancer dormancy, drug resistance, epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET), and cancer stem cell plasticity. As CSC may underlie resistance to therapy and cancer metastasis, understanding how cell division mode is selected and executed in these cells will provide possible strategies to target CSC.