Evolutionary Chemistry Approach toward Finding Novel Inhibitors of the Type 2 Diabetes Target Glucose-6-phosphate Translocase

Abstract

A genetic algorithm (GA), driven by experimentally determined biological activities as a feedback fitness function, was used to propose novel small molecules as inhibitors of glucose-6-phosphate translocase (G6PT) in iterative rounds of evolutionary optimization. A straightforward polymer-supported synthetic sequence was implemented to synthesize molecules proposed by the GA, and the biological activities of the compounds were determined by a microsomal assay. Additional compound design strategies were integrated, such as Tanimoto similarity-based selection of starting materials and transfer of favored structure elements into a new chemical scaffold to identify more active and selective inhibitors.

Silencing of the human microsomal glucose‐6‐phosphate translocase induces glioma cell death: Potential new anticancer target for curcumin

“…Consequently, specific interference with G6PT functions [8,15] or expression [this study] becomes an attractive strategy for therapeutic control of glioma cell growth, and selective inhibition of G6PT may provide an ideal approach for the metabolic regulation of brain tumor cells. Several inhibitors of G6PT have been reported [32–36] and include complex natural products such as ilicicolinic acid B, hericenal C, mumbaistatin, kodaistatins [37], and derivatives of CHA [11]. Aside from CHA, few of these documented G6PT inhibitors have been systematically tested for their anti‐cancer properties.…”

Chemistry and Biology Of Multicomponent Reactions

“…25). 134 Different scaffold spaces based on vL-3CR and reductive amination/acylation chemistries were investigated. Within the performed evolutionary cycles of synthesis, analytics, screening, and library design, promising lead structures were found.…”

Silencing of the MT1‐MMP/ G6PT axis suppresses calcium mobilization by sphingosine‐1‐phosphate in glioblastoma cells

“…These findings, along with G6PT's endoplasmic/sarcoplasmic reticulum Ca 2+ sequestration function [14], demonstrate that G6PT is not just a G6P transport protein but may also potentially contribute to intracellular Ca 2+ homeostasis. This explains, in part, why chlorogenic acid (CHL), among the most potent functional inhibitor of G6PT [15], inhibited S1P‐induced glioblastoma cell migration as well as the rapid, S1P‐induced ERK phosphorylation in glioblastoma cells [16].…”