Transcript-specific ablation of SSD-regulated alternative spliced products with CIRSPR-Cas13 or targeting PIM1/Myc with specific small inhibitors significantly desensitizes cancer cells and patient-derived organoids (PDOs) to SSD treatments. These studies demonstrated the potent anti-tumor efficacy of SSD and exposed a PIM1/Myc axis by which SSD modulates the expression of an oncogenic alternative splicing regulatory network that mediates SSD's anti-tumor role in cancers.

Compound 4d exhibited a 1.5-fold increased cytotoxic activity compared to doxorubicin against the MCF-7 cell line, whereas compound 9a showed an analogous activity to doxorubicin...Besides, docking of the desired compounds into Pim-1 ATP binding site showed a noteworthy binding mode for the enzyme inhibition. Additionally, a 2D QSAR identified the potential structural features controlling the Pim-1 inhibitory activity attained via the targeted pyrazolo[1,5-a]pyrimidines.

Compound 15 demonstrated the strongest anticancer activity, with IC50 value of 34.49 ± 1.32 μM, compared to doxorubicin (IC50 = 34.20 ± 0.28 μM)...Additionally, the binding relationships produced between compound 15 and the PIM-1 kinase active site were investigated using molecular docking experiments, providing insights into their inhibitory potential. Finally, to further assess the stability of the compound 15-PIM-1 kinase complex and validate the docking results, molecular dynamics (MD) simulations were performed.

The expression of circRNAs 0076215 and 0076216, validated for the first time in a set of 19 physiological human tissues, positively correlated with that of their host gene (Rho value = 0.579 and 0.681, p-value = 0.026 and 0.013, respectively). Our data suggest that PIM1 is an oncogene involved in the recurrence of WHO grade 2 MNG and that the upstream ceRNA network, comprising circRNAs 0076215 and 0076216 and miRNAs 16-5p and 195-5p, is responsible for its upregulation through a feed-forward loop.

We then explored the effects of the selective PIM1 inhibitor TP-3654 on fibrosis...Downregulation of PIM1 expression in fibroblasts using drugs or siRNA leads to decreased ENO1 expression, concurrent with AKT phosphorylation reduction and suppressor of mothers against decapentaplegic (Smad)2/3 dephosphorylation within the TGF-β classical pathway. In summary, PIM1 might be an important target gene for future skeletal muscle atrophy treatments.

Recently, targeting TrkA gained attention following FDA approval of entrectinib and larotrectinib for NSCLC. Compounds 6e and 7f emerged as the most balanced inhibitors of PIM-1 (IC50 = 3.9 nM, 4.6 nM), CDK2, and TrkA. Molecular docking and dynamics simulations highlighted key interactions stabilizing these compounds, which disrupted the A549 cell cycle and induced apoptosis by over 30%.

Strikingly, IBL-202 strongly induced cell-cycle-dependent cell death in cell lines of different mTCL subtypes. Together, our study provides mechanistic evidence supporting a therapeutic strategy of dual Pim- and PI3-kinase inhibition in mature T-cell lymphoma.

Repurposing FDA approved drugs with off-target autophagy inhibition such as chloroquine/hydroxychloroquine (CQ, HCQ) has produced modest anticancer activity in clinical trials, due in part, to a failure to define predictive biomarkers that enable the selection of patients that best respond to this treatment strategy. Inhibition of autophagy with CQ synergistically enhanced the in vitro and in vivo anticancer activity of TP-3654. Our findings identify REDD1 as a novel determinant of the sensitivity of RCC cells to autophagy inhibition and support further investigation of PIM kinase inhibition as a precision strategy to drive sensitivity to autophagy-targeted therapies through REDD1 upregulation.

Moreover, Quer reduced Rop-induced cytotoxicity by stimulating autophagy in SH-SY5Y cells by targeting the Pim1 protein, which was accomplished via the AMPK/mTOR pathway. Quer relieved Rop-induced neurotoxicity in SH-SY5Y cells through upregulating Pim1 and enhancing autophagy, indicating that Quer may have potential therapeutic applications in the treatment of Rop-induced neurotoxicities.

Furthermore, SNHG21 bind to PIM1 proteins and prevented it from ubiquitin-protease dependent degradation and ultimately enhancing mitochondrial homeostasis. Overall, our study indicates the RBM19/SNHG21/PIM1 axis may be the encouraging target for docetaxel-tolerance PCa treatment.

Four drugs, stanozolol, alfaxalone, rifaximin, and telmisartan, were identified as strong PIM-1 binders, interacting with key residues in the ATP-binding pocket of the kinase. Our findings suggest that rifaximin may serve as a potential repurposed therapeutic for targeting PIM-1 in cancer treatment. However, further validations are required in a clinical setting before the final therapeutic implications.

This makes ZINC00388658 the most promising candidate for further development as a PIM-1 inhibitor. These findings suggest that ZINC00388658 and other promising compounds hold significant potential for developing new cancer therapies that target PIM-1.