TABLE 1

Small-molecule inhibitors of mRNA translation and upstream pathwaysa

TargetInhibitor(s)Mechanism of action
mTORC1Rapamycin (sirolimus), everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP23573)Rapamycin and the rapalogues bind to FKBP12, which allows the formation of a ternary complex with mTOR; the rapamycin-FKBP12 dimer binds mTOR outside its kinase domain, and it is believed that this interaction interferes with the binding of mTOR and its substrates
PI3K/mTORBEZ235 (dactolisib), PI-103, XL765 (voxtalisib), BGT226, PF-05212384 (gedatolisib)ATP-competitive inhibitors of mTOR and PI3K (multiple isoforms)
mTORC1/2MLN0128 (sapanisertib), AZD8055, Torin1, PP242 (torkinib), OSI-027, Rapa-Link1ATP-competitive inhibitors of mTOR (inhibit either mTORC1 or mTORC2) (Rapa-Link1 simultaneously acts as ATP-competitive and allosteric inhibitor)
PI3KBKM120 (buparlisib), GDC-0941 (pictilisib), BAY 80-6946 (copanlisib), ZSTK474, GDC-0032 (taselisib)Pan-class I PI3K ATP-competitive inhibitors
BYL719 (alpelisib), SAR260301, GS-1101 (idelalisib), INCB040093, AMG319, TGR-1202, IPI-145 (duvelisib), GSK2636771Isoform-specific PI3K ATP-competitive inhibitors
AKTMK2206Pleckstrin homology domain-dependent allosteric inhibitor of AKT that promotes AKT relocalization to the cytoplasm and prevents its phosphorylation by PDK1 and mTORC2; MK2206 is more selective toward AKT1/2 than toward AKT3
KRX-0401 (perifosine)Alkyl-phosphocholine that targets cellular membranes and thereby inhibits AKT activation, as well as many other membrane-dependent events
GSK690693ATP-competitive inhibitor of Akt1/2/3
GDC-0068 (ipatasertib)Non-ATP-competitive inhibitor of Akt1/2/3
S6K1PF-4708671Inhibits S6K1-dependent phosphorylation of substrates; mechanism of action is unavailable
LY2584702ATP-competitive inhibitor of S6K1
MNKeFT508ATP-competitive inhibitor of MNK1/2
BAY 1143269MNK1 inhibitor with undisclosed mechanism of action
Cercosporamide, CGP57380, CGP052088Poorly selective MNK inhibitors that target the ATP-binding domain of MNK1/2
RSKLJH685 (and related LJI308), SL0101, BI-D1870ATP-competitive inhibitor of the RSK N-terminal kinase domain
FMKCovalent inhibitor of the C-terminal kinase domain of RSK1/2/4
eIF4ELY2275796Reduction of eIF4E expression using antisense oligonucleotide
Cap analogues, including 4Ei-1Inhibition of eIF4E binding to 5′ cap of mRNA
4EGI-1, 4E1RCat, 4E2RCatInhibition of eIF4E-eIF4G interaction
eIF4ASilvestrol, hippuristanol, pateamine AInhibition of eIF4A helicase activity
  • a This table includes selected small-molecule inhibitors that target components of the translation machinery (eIF4E and eIF4A) or upstream pathways involved in translational control (mTOR, PI3K, AKT, S6K, MNK, and RSK).