CMLD012073, an Amidino-Rocaglates, is a Potent eIF4A Inhibitor
Posted On 2020-09-25
The eukaryotic translation initiation factors 4A (eIF4A) is crucial for the assembly of the translationally active ribosome. Especially, the eIF4A is an RNA helicase that forms part of the machinery of translation initiation. Small molecules targeting the translation machinery show considerable promise in the treatment of a variety of human maladies including cancer, viral infection, and neurodegeneration.
CMLD012073 is an amidino-rocaglate, and is a potent inhibitor of translation. Rocaglates share a common cyclopenta[b]benzofuran core that inhibits eukaryotic translation initiation by modifying the behavior of the RNA helicase, eIF4A. In particular, CMLD012073 bearing a methyl (Me) group exhibits an IC50 of 10 nM. Moreover, CMLD012073 is ∼3-fold more potent at inhibiting cap-dependent translation than CR-1-31-B in vitro translation assays. In ribosome recruitment experiments, CMLD012073 inhibits assembly of the 80S ribosome on the mRNA, thus further supporting the notion that this compound acts as an inhibitor of initiation.
The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. In addition, these proteins are helicases that function to unwind double-stranded RNA. Furthermore, CMLD012073 is an amidino-rocaglates and is a potent eukaryotic initiation factor 4A (eIF4A) inhibitor. In particular, rocailles are a class of translation inhibitors that possess potent cytotoxic activity against tumor cells.
In summary, The translation initiation factor eIF4A is the founding member of the DEAD-box protein family. The eIF4A is an RNA-stimulated ATPase and a non-processive helicase that unwinds short RNA duplexes. CMLD012073 inhibits eukaryotic translation initiation by modifying the behavior of the RNA helicase (eIF4A). Amidino- and amino-rocaglates act as potent translation inhibitors and anti-cancer agents.
Jennifer Chu, et al. Amidino-Rocaglates: A Potent Class of eIF4A Inhibitors. Cell Chem Biol. 2019 Nov 21;26(11):1586-1593.e3.