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Morpholino nicotinamide analogs of ponatinib, dual MNK, p70S6K inhibitors, display efficacy against lung and breast cancers

Year: 2025

Type: article

Abstract: Therapeutic options for aggressive cancer types such as breast and lung remain limited; disease relapse and death occur in 30–60% of non-small cell lung cancer (NSCLC) patients, whereas in triple-negative breast cancer or TNBC, recurrence-free survival occurs in less than 30% patients. The kinases, MNK and p70S6K have been proposed as targets for the potential treatment of breast cancer (BC) and lung cancer but currently, no drug that was purposely designed to inhibit these kinases have been approved by the FDA for the treatment of BC or NSCLC. In this study, we have identified HSND80 (a morpholino nicotinamide analog of ponatinib) as a potent MNK/p70S6K inhibitor that has excellent activity against TNBC and NSCLC cell lines. HSND80 has a longer target residence time (τ) of 45 mins and 58 mins against MNK1 and MNK2 respectively, compared to τ of eFT508 (tomivosertib) against MNK1 and MNK2 (τ = 1 min and 5 min, respectively). Molecular dynamics simulation was used to provide some insights into the binding of HSND80 to MNK and p70S6K kinases. Western blotting analysis and phosphoproteomics analysis of the TNBC cell line, MDA-MB-231, revealed that phosphorylations of elF4E (MNK target) and elF4B and S6 (p70S6K targets) were reduced upon compound treatment, which is in line with the proposed mechanism of action; dual MNK/p70S6K targeting. HSND80 could be dosed orally at 15 and 30 mg/kg and at such doses, could reduce tumor volume in a syngeneic NSCLC mouse model. • Alkynyl imidazo[1,2- b ]pyridazine compounds bearing morpholino groups are dual MNK/p70S6K inhibitors. • HSND80 , the lead compound of this study, has a longer target residence time (τ) of 45 mins and 58 mins against MNK1 and MNK2 respectively, compared to τ of eFT508 (tomivosertib) against MNK1 and MNK2 (τ = 1 min and 5 mins, respectively). • HSND80 inhibited several breast and lung cancer cell lines with nanomolar IC 50 values. • HSND80 inhibited NSCLC syngeneic model KLN 205 in vivo (mice).

Source: Bioorganic Chemistry

DOI: 10.1016/j.bioorg.2025.108298