Optimization of 4,6-Disubstituted Pyrido[3,2-d]pyrimidines as Dual MNK/PIM Inhibitors to Inhibit Leukemia Cell Growth

Abstract

Mitogen-activated protein kinase-interacting kinases (MNKs) and provirus integration in maloney murine leukemia virus kinases (PIMs) are downstream enzymes of cell proliferation signaling pathways associated with the resistance of tyrosine kinase inhibitors. MNKs and PIMs have complementary effects to regulate cap-dependent translation of oncoproteins. Dual inhibitors of MNKs and PIMs have not been developed. We developed a novel 4,6-disubstituted pyrido­[3,2-d]­pyrimidine compound 21o with selective inhibition of MNKs and PIMs. The IC50’s of 21o to inhibit MNK1 and MNK2 are 1 and 7 nM and those to inhibit PIM1, PIM2, and PIM3 are 43, 232, and 774 nM, respectively. 21o inhibits the growth of myeloid leukemia K562 and MOLM-13 cells with GI50’s of 2.1 and 1.2 μM, respectively. 21o decreases the levels of p-eIF4E and p-4EBP1, the downstream products of MNKs and PIMs, as well as cap-dependent proteins c-myc, cyclin D1, and Mcl-1. 21o inhibits the growth of MOLM-13 cell xenografts without causing evident toxicity. 21o represents an innovative dual MNK/PIM inhibitor with a good pharmacokinetic profile.

Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies

“…PIM kinases are proto-oncogenic serine/threonine kinases that comprise three PIM 1, 2, and 3 homologous proteins with high levels of functional similarity, however, they differ in their distribution in tissues (Jiménez-garcía et al, 2016;Han et al, 2021). Both isoforms 1 and 2 are upregulated in several malignant hematological tumors, including AML, chronic lymphocytic leukemia, acute lymphoblastic leukemia, multiple myeloma, and non-Hodgkin lymphoma (Keeton et al, 2014).…”

“…Unfortunately, the majority of PIM inhibitors show little or no effect when administered as a single drug, due to the rapid resistance produced by redundancy or feedback signaling (Nawijn et al, 2011;Tursynbay et al, 2016). Therefore, it is urgent to identify drug combinations to prevent resistance to therapy such as inhibitors of PIM kinase in combination with inhibitors of MNK (Han et al, 2021).…”

“…MNK1 and MNK2 (MAPK-interacting kinases 1 and 2) are the only kinases that phosphorylate the eukaryotic translation initiation factor 4E (eIF4E), which is required for cell development, death, and metastasis (Dreas et al, 2017;Han et al, 2021). Such a phosphorylation is the rate-limiting factor in the initiation of mRNA translation and is important in the malignant transformation process (Fischer, 2009).…”

“…Due to the participation of eIF4E in both the RAS/RAF/ERK and the PI3K/AKT/mTOR pathways, inhibiting its phosphorylation could decrease imipenemase (IMP) linked resistance. Therefore, PIM inhibition in combination with MNKs inhibitors may have a synergistic effect on AML cells (Han et al, 2021). Inhibition of both MNK and PIM is less likely to be associated with adverse side effects, and they may have minimal or no hematopoietic defects in mice (Kapelko-slowik et al, 2016).…”

Chemistry and biological evaluation of pyrido[4,3‐d]pyrimidines: A review

“…Pyridopyrimidine also has a valuable source of intermediates, and pyrido[4,3‐ d ]pyrimidine acts as a pharmacophore of drug development. The N‐fused heterocyclic molecules as pyridopyrimidine are one of the interesting fused heterocyclic moieties leading to the synthesis and colossal pharmacological applications (Han et al, 2021; Voskressensky et al, 2005). In pyridopyrimidine compounds, a pyridine ring is directly fused to the pyrimidine ring, there are numerous classes of possible isomeric forms, and pyridopyrimidine derivatives are the ones already mentioned (Figure 1).…”