Novel eIF4A1 inhibitors with anti‐tumor activity in lymphoma

Abstract

Background Deregulated translation initiation is implicated extensively in cancer initiation and progression. It is actively pursued as a viable target that circumvents the dependency on oncogenic signaling, a significant factor in current strategies. Eukaryotic translation initiation factor (eIF) 4A plays an essential role in translation initiation by unwinding the secondary structure of messenger RNA (mRNA) upstream of the start codon, enabling active ribosomal recruitment on the downstream genes. Several natural product molecules with similar scaffolds, such as Rocaglamide A (RocA), targeting eIF4A have been reported in the last decade. However, their clinical utilization is still elusive due to several pharmacological limitations. In this study we identified new eIF4A1 inhibitors and their possible mechanisms. Methods In this report, we conducted a pharmacophore-based virtual screen of RocA complexed with eIF4A and a polypurine RNA strand for novel eIF4A inhibitors from commercially available compounds in the MolPort Database. We performed target-based screening and optimization of active pharmacophores. We assessed the effects of novel compounds on biochemical and cell-based assays for efficacy and mechanistic evaluation. Results We validated three new potent eIF4A inhibitors, RBF197, RBF 203, and RBF 208, which decreased diffuse large B-cell lymphoma (DLBCL) cell viability. Biochemical and cellular studies, molecular docking, and functional assays revealed that thosenovel compounds clamp eIF4A into mRNA in an ATP-independent manner. Moreover, we found that RBF197 and RBF208 significantly depressed eIF4A-dependent oncogene expression as well as the colony formation capacity of DLBCL. Interestingly, exposure of these compounds to non-malignant cells had only minimal impact on their growth and viability. Conclusions Identified compounds suggest a new strategy for designing novel eIF4A inhibitors.

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“…1F , top). Among the top downregulated genes were FOS, JUN, ATF3, ATF4, NFKBIA and MAP3K8 which are essential for the growth of B lymphocytes 20 , 21 as well as proteins of the EIF (eukaryotic initiation factor) family (EIF4A1 22 , EIF4A2, EIF4A3), GADD34 23 , ribosomal protein L family (RPL4, RPL9, RPL13, RPL21, RP23, PRL27, RPL37, RPL38, RPL10A) and ribosomal proteins family (RPS2, RPS6, RPS9, RPS11, RPS16, RPS20, RPS26, RPS27) which are essential for lymphoma cell proliferation and protein synthesis 24 ( Fig. 1F , top).…”

eIF4F complex dynamics are important for the activation of the integrated stress response

“…Emerging from several studies is the observation that overexpression of eIF4F subunits leads to tumorigenesis. 86 – 88 Notably, most tumors display pronounced overexpression of eIF4A relative to eIF4E. Although eIF4A is overexpressed ~15-fold on average, eIF4E levels are not significantly changed (1.28-fold) in human primary cancers.…”

HINT, a code for understanding the interaction between biomolecules: a tribute to Donald J. Abraham

“…Among the 17 compounds selected for testing, two showed IC 50 s in the low μM range, identifying interesting hits for the development of novel antimicrobials ( Spyrakis et al, 2014 ). 3) The most recent publication using HINT in this way ( Kayastha et al, 2022 ) details the discovery of three new potent eIF4A inhibitors that diminished the viability of diffuse large B-cell lymphoma (DLBCL) cells. The actives were discovered via target-based virtual screening in the MolPort database, followed by pharmacophore-based and analog screening.…”