Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

Abstract

Targeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. However, most of the advanced inhibitors are acting in an adenosine triphosphate (ATP)-competitive mode, precluding the evaluation of different binding modes in preclinical settings. Using rational design, we identified and validated the 4,6-diaryl-pyrazolo[3,4- b ]pyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathway analysis confirmed a direct effect of the hit compound EB1 on MNKs, and in line with the reported function of these kinases, EB1 only affects the growth of tumor but not normal cells. Molecular modeling revealed the binding of EB1 to the inactive conformation of MNK1 and the interaction with the specific DFD motif. This novel mode of action appears to be superior to the ATP-competitive inhibitors, which render the protein in a pseudo-active state. Overcoming this paradoxical activation of MNKs by EB1 represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.

MNK Proteins as Therapeutic Targets in Leukemia

“…Bou-Petit et al designed EB1 which has a 4,6-diaryl-1H-pyrazolo[3,4-b]pyridin-3-amine core structure and binds to the inactive MNK1 with an IC 50 of 0.69 μM (MNK2 IC 50 = 9.4 μM) preventing transition to its active state and demonstrated reduction of phosphorylation of Ser209 on eIF4E in various cell lines including MV411 AML cells. 58 Interestingly, the authors demonstrated that EB1 did not induce upstream activation and phosphorylation of MNK1 leading to enhanced binding to eIF4G as did the type I inhibitors tested in comparison. These results highlight the potential benefits of a type II inhibitor in that it would not lead to paradoxical target protein activation induced by some type I kinase inhibitors which occurs even with catalytic kinase activity inhibition.…”

Medicinal chemistry approaches to target the MNK–eIF4E axis in cancer

“…90,91,[110][111][112] To identify non-ATP-competitive MNK inhibitors, Bou-Petit and coworkers looked into alternate scaffolds without the ability to directly interact at the ATP binding site. 113 They reported a new pyrazolo [3,4-b]pyridine-3-amine scaffold with potent MNK inhibitory activity, which was identified from a radiometric protein kinase assay. 113 Their initial efforts were focused on the development of a series of pyrazolo [3,4-b] pyridine-6-one compounds.…”

“…113 They reported a new pyrazolo[3,4- b ]pyridine-3-amine scaffold with potent MNK inhibitory activity, which was identified from a radiometric protein kinase assay. 113 Their initial efforts were focused on the development of a series of pyrazolo[3,4- b ]pyridine-6-one compounds. However, since these were inactive, a series of pyrazolo[3,4- b ]pyridine-3-amine compounds were synthesized (Fig.…”

Autocatalytic photoinduced oxidative dehydrogenation of pyrido[2,3-d]pyrimidin-7(8H)-ones: synthesis of C5–C6 unsaturated systems with concomitant formation of a long-lived radical

“…Our research group has been actively working in the field of Tyrosine Kinase Inhibitors (TKIs) with the aim of developing drug candidates against diverse types of cancers such as breakpoint cluster region protein (BCR) kinase inhibitors for B lymphoid malignancies, 1 discoidin domain-containing receptor 2 (DDR2) inhibitors for the treatment of lung cancer, 2 MAP kinase interacting kinase (MNK1/2) inhibitors for the treatment of breast or prostate cancer, 3 zeta-chain-associated protein kinase 70 kDa (ZAP-70) inhibitors, 4 and more recently a promising candidate for the treatment of pancreatic cancer (unpublished results).…”