Shenzhen Zhenxing Pharmaceutical Technology Co Ltd

Triple-negative breast cancer (TNBC) is an aggressive subtype that primarily relies on chemotherapy. Natural products like magnolol and sulforaphane, especially their synthetic hybrid, have shown promising antitumor activity. To develop more potent agents, we designed and synthesized 15 novel magnolol-sulforaphane hybrid analogues and evaluated their anticancer efficacy. Among them, compound 17a demonstrated the highest potency, exhibiting an average 7.4-fold increase in antiproliferative activity with IC₅₀ values ranging from 0.85 ± 0.04 μM to 1.34 ± 0.02 μM in TNBC cell lines compared to the parent hybrid CT1-3. In vitro, 17a significantly suppressed TNBC cell proliferation, colony formation, migration, and invasion while inducing apoptosis. In vivo, administration of 17a effectively inhibited tumor growth without apparent toxicity in an MDA-MB-231 xenograft model, as evidenced by normal organ morphology. Mechanistically, RNA sequencing revealed that 17a downregulated the nucleotide excision repair (NER) and NF-κB pathways, suppressing expression of NER-related genes (ERCC2, POLE2, LIG1, GTF2H3, and DDB2) at mRNA and protein levels and inhibiting phosphorylation of IKKα and p65. These findings position 17a as a potent therapeutic candidate for TNBC treatment, warranting further clinical investigation.

Despite a standard of care, the mortality of recurrent high-grade gliomas (HGGs) remains high. SM-1 is a novel molecular activator that has shown to target procaspase-3, which is overexpressed in HGGs. A phase I clinical trial was conducted to evaluate the safety, pharmacokinetics, and primary clinical efficacy of SM-1 plus TMZ. Participants received escalating doses of daily oral SM-1 (450, 600, and 800 mg) plus standard TMZ therapy.

In the preclinical study, the synergistic effects of SM-1 and temozolomide (TMZ) in rodent models were evaluated. In the clinical study, adult patients received SM-1 therapy in various doses in combination with a standard TMZ dosing. The tolerability and pharmacokinetics data of the combination therapy were tested. The primary efficacy was measured by tumor response in accordance with the RANO criteria.

A total of 13 patients with recurrent HGG were enrolled, with 11 patients completed ≥ two cycles of therapy and received tumor assessment. Among them, one patient had complete response, whereas two patients had partial response for the best change from baseline. No dose-limited toxicities were observed, and no maximum tolerated dose was reached.

SM-1 has the potential to enhance antitumor activity while alleviating the side effects of TMZ. SM-1 exhibited mild toxicity in patients with recurrent HGG. The combination of SM-1 and TMZ warrants further investigation, with promising clinical outcomes. The monotherapy phase and expansion phase of SM-1 are still ongoing. (ClinicalTrials.gov number, CTR20221641).

Head and neck squamous cell carcinoma (HNSCC) is globally prevalent with high recurrence, low survival rate, and poor quality of life for patients. Derived from PAC-1, SM-1 can activate procaspase-3 and induce apoptosis in cancer cells to exert anti-tumor effects. However, the inhibitory effect of SM-1 on HNSCC after combination with radiation are unclear. This study aims to investigate the radiosensitizing effect of SM-1 on HNSCC in vitro and in vivo.

MTT method was used to detect the effect of SM-1 on the viability of HNSCC cell lines (HONE1, HSC-2, and CAL27). The effects of SM-1 combined with radiation on the survival index of HONE1, HSC-2, and CAL27 cell lines were determined by colony formation assay. Flow cytometry was used to investigate the effects of SM-1 and radiation combination on cell apoptosis and cell cycle, and western blot experiments were performed to detect the expression of apoptosis and cell cycle-related proteins. Finally, a xenograft tumor model of CAL27 was established to evaluate the anti-tumor effect of SM-1 combined with radiation in vivo.

In vitro, SM-1 effectively inhibited the activity of HNSCC cell lines HONE1, HSC-2, and CAL27 cells, and synergistically showed anti-proliferation activity during combined irradiation. Meanwhile, anti-tumor effect of SM-1 on HNSCC was higher than that of Debio1143, and the radiosensitivity of cells was greatly increased. Flow cytometry and western blot analysis showed that SM-1 induced G2/M phase arrest of head and neck squamous cell carcinoma cells via inhibiting the expression of CyclinB1 and CDC2. Moreover, SM-1 activated caspase-3 activity and up-regulated the cleaved form of PARP1 to induce cell apoptosis. In vivo, SM-1 combined irradiation showed a good anti-tumor effect.

SM-1 enhances HNSCC cell radiation sensitivity in vitro and in vivo, supporting its potential as a radiosensitizer for clinical trials in combination with radiotherapy.