Advances in Small Molecules in Cellular Reprogramming: Effects, Structures, and Mechanisms

Abstract

The method of cellular reprogramming using small molecules involves the manipulation of somatic cells to generate desired cell types under chemically limited conditions, thus avoiding the ethical controversy of embryonic stem cells and the potential hazards of gene manipulation. The combinations of small molecules and their effects on mouse and human somatic cells are similar. Several small molecules, including CHIR99021, 616452, A83-01, SB431542, forskolin, tranylcypromine and valproic acid [VPA], have been frequently used in reprogramming of mouse and human somatic cells. This indicated that the reprogramming approaches related to these compounds were essential. These approaches were mainly divided into four classes: epigenetic modification, signal modulation, metabolic modulation and senescent suppression. The structures and functions of small molecules involved in these reprogramming approaches have been studied extensively. Molecular docking gave insights into the mechanisms and structural specificities of various small molecules in the epigenetic modification. The binding modes of RG108, Bix01294, tranylcypromine and VPA with their corresponding proteins clearly illustrated the interactions between these compounds and the active sites of the proteins. Glycogen synthase kinase 3β [CHIR99021], transforming growth factor β [616452, A83-01 and SB431542] and protein kinase A [forskolin] signaling pathway play important roles in signal modulation during reprogramming, however, the mechanisms and structural specificities of these inhibitors are still unknown. Further, the numbers of small molecules in the approaches of metabolic modulation and senescent suppression were too few to compare. This review aims to serve as a reference for reprogramming through small molecules in order to benefit future regenerative medicine and clinical drug discovery.