STAT3 x Tubulin

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder, requiring multitarget-directed ligands capable of modulating interconnected pathological pathways. Here, a pharmacophore-hybridization strategy combining COX-2-selective 1,5-diarylpyrazole scaffolds with a zinc-binding group was used to design dual COX-2/HDAC6 inhibitors. Twenty hybrids were synthesized and evaluated, identifying 10a and 11e as the most potent compounds, with IC₅₀ values of 0.18 and 0.66 μM for COX-2, and 0.15, 0.12 μM for HDAC6, respectively. Molecular dynamics simulations confirmed stable binding of 11e to both enzymes, with persistent hydrogen bonding, minimal RMSD fluctuations, and favorable binding free energies (ΔG_bind = -29.3 and -51.5 kcal/mol for HDAC6 and COX-2, respectively). Compound 11e exhibited potent neuroprotective activity by markedly enhancing α-tubulin acetylation, suppressing the expression of pro-inflammatory mediators (COX-2, IL-1β, IL-6, and TNF-α), promoting amyloid-β clearance, restoring memory-related gene expression, and significantly reducing Tau hyperphosphorylation. Histopathological analyses confirmed decreased phosphorylated STAT3 and Tau levels, preserved neuronal morphology via MAP2 stabilization, and protection of synaptic integrity through synaptophysin regulation. Behavioral studies in a scopolamine-induced AD mouse model demonstrated substantial improvements in learning and memory. These findings establish 11e as a potent dual COX-2/HDAC6 inhibitor and a promising multitarget scaffold for developing disease-modifying therapies for AD and related neurodegenerative disorders.

Microtubule-targeting agents constitute a cornerstone of cancer chemotherapy, yet drug resistance remains a major challenge. Signal transducer and activator of transcription-3 (STAT3) inhibition may potentiate chemosensitivity and circumvent resistance mechanisms. During a phenotypic screen of anticancer agents, a small-molecule compound IMB5023 emerged as a promising candidate. In the present work, we report its antitumor efficacy and mechanism of action. IMB5023 exhibited cytotoxicity across multiple cancer cell lines, inducing pyroptosis in gasdermin E-positive cells and apoptosis in gasdermin E-negative cells. Transcriptomic profiling revealed that IMB5023 targeted centrosome-related pathway and impaired mitotic spindle assembly. Immunofluorescence analysis revealed concentration-dependent effects: multipolar spindle formation at a low concentration (1 μM) and microtubule network disruption at a higher concentration (10 μM). Furthermore, IMB5023 suppressed STAT3 pathway in vitro and overcame multidrug resistance by downregulating drug efflux pump ATP-binding cassette sub-family G member 2 (ABCG2) and anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL). Notably, IMB5023 triggered immunogenic cell death and enhanced dendritic cell phagocytosis. In vivo, IMB5023 inhibited tumor growth by 52%. Tumor histopathology confirmed centrosome declustering and STAT3 pathway inhibition. Collectively, IMB5023 concurrently disrupts microtubules and inhibits STAT3 pathway. This dual mechanisms of action positions IMB5023 as a promising therapeutic candidate, particularly for resistant malignancies.

Metastasis is the primary challenge in lung cancer treatment. Although proteostasis supports tumor growth, the mechanism by which ubiquitin ligases reprogram chaperone networks to drive metastasis is poorly understood. In this study, it is revealed that DDB1‐CUL4‐associated factor (DCAF12), a substrate receptor for CUL4‐RING ubiquitin ligases, regulates metastatic progression through ubiquitin‐mediated proteostatic reprogramming. DCAF12 depletion suppresses tumor cell migration and stemness in vitro and reduces pulmonary/hepatic metastasis in vivo. Mechanistically, DCAF12 catalyzes the non‐degradative ubiquitination of TRiC/CCT subunits, enhancing chaperonin assembly and folding of cytoskeletal effectors (β‐actin/tubulin) and oncogenic clients (STAT3/Raptor/mLST8), thereby activating the YAP, STAT3, and mTOR pathways. Both genetic knockdown and pharmacological blockade (via HSF1A) of this axis potently inhibit metastasis. Clinically, DCAF12 overexpression is correlated with YAP/STAT3 activation, advanced metastasis, and poor survival. Three key insights are revealed: 1) ubiquitination‐mediated TRiC/CCT regulation as a metastatic switch, 2) DCAF12 as an oncogenic proteostasis hub, and 3) therapeutic potential validated through multimodal targeting. These findings establish the DCAF12‐TRiC/CCT axis as a mechanistically novel target that simultaneously disrupts cytoskeletal dynamics and oncogenic signaling, making it a promising therapeutic strategy for metastatic lung cancer.