STAT3 inhibitors(Zhejiang Chinese Medical University)

Intrinsic and acquired resistance to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) remains a major barrier in treating homologous recombination (HR) repair-deficient tumors, including those with germline or somatic BRCA1/2 mutations. Although PARPi are FDA approved for adjuvant treatment of locally advanced or metastatic breast cancer in patients with germline BRCA1/2 mutations, emerging data support their use as monotherapy in the neoadjuvant setting. Promising safety profiles of newer-generation PARPi further support this potential. However, resistance mechanisms specific to the neoadjuvant setting are poorly understood. To address this gap, we leveraged resources from a phase II neoadjuvant clinical trial (NCT03499353), analyzing tumors from patients with germline BRCA1/2 mutant breast tumors before and after six months of talazoparib monotherapy. Whole-transcriptome analyses were performed on these samples. Additionally, we established orthotopic patient-derived xenograft models from a subset of the patient tumors and conducted whole-exome and whole-transcriptome analysis. This integrative approach revealed both known and previously unknown PARPi resistance mechanisms. In one case, overexpression of BRN2 , encoding a transcription factor that plays a critical role in neurogenesis, led to activation of ATR/RAD51 and STAT3 pathways, restoring HR repair. BRN2-driven resistance could be reversed with ATR and STAT3 inhibitors, resensitizing cells to talazoparib. In another, an HR repair proficient tumor subclone lacking Shieldin 2 expression expanded during treatment and accounted for intrinsic resistance. Our findings highlight the need to determine intrinsic and anticipate acquired resistance pathways in treatment-naïve tumors and support combining PARPi with targeted agents to improve outcomes in the neoadjuvant setting.

To identify potent candidate drugs for colorectal cancer (CRC), a series of N-benzimidazole-1,3,4-thiadiazole-2-amine derivatives featuring diverse ester groups were designed and synthesized, based on our preceding research. Systematic pharmacological evaluation demonstrated their inhibitory effects against the IL-6/JAK/STAT3 signaling pathway and CRC cell lines with constitutively activated STAT3. Among these derivatives, compound L20 demonstrated the most potent anti-proliferative activity against HCT116 (IC₅₀ = 0.45 ± 0.05 μM) and other CRC-relevant cell lines. Mechanistic investigations confirmed that L20 directly binds to STAT3 protein (K_D = 6.16 μM), specifically interacting with its SH2 domain. This binding resulted in a dose-dependent suppression of STAT3 phosphorylation at Y705 without affecting total STAT3 protein levels. Furthermore, L20 dose-dependently downregulated both the transcription and expression of cyclin-D1 and c-Myc, two critical downstream effectors of STAT3. Additionally, it induced cell cycle arrest and promoted apoptosis in HCT116 cells in a concentration-dependent manner. Notably, in a murine MC38 subcutaneous xenograft model, L20 administration (20 mg/kg, i.p.) significantly suppressed tumor growth, achieving a tumor growth inhibition rate of 59.8 %. These results highlight the promise of L20 as a novel candidate for CRC therapy and establish a compelling basis for the continued develop of STAT3-targeted interventions against CRC.