PAC-1

Derived from PAC-1, SM-1 can activate procaspase-3 and induce apoptosis in cancer cells to exert anti-tumor effects...Meanwhile, anti-tumor effect of SM-1 on HNSCC was higher than that of Debio1143, and the radiosensitivity of cells was greatly increased...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.

Prophylactic transfusion improved platelet function. Platelet function significantly improved in patients with a CCI >4500, those with the same blood types as that of apheresis platelets, or those with platelet-derived microparticle levels <4.7%. No significant improvement in platelet function was noted after the transfusion of different blood types with acceptable compatibility or the transfusion of incompatible blood types. Our results suggest that transfusing platelets with the same blood type remains the optimal choice.

A platelet aggregation assay was performed, and the expression of P-selectin and PAC-1, as well as the effect on the proliferation of healthy endothelial cells, were evaluated. All the analogues reduced the expression of E- and N-cadherin in different amounts, while the analogues-1 and -3 exhibited similar antimigratory effects on HepG2 cells. The results of this study reveal considerable potential to develop new tyrosine kinase inhibitors with improved antiplatelet and antitumor properties.

P1/2, N=6, Terminated, Arkadiusz Z. Dudek, MD | Phase classification: P1b/2 --> P1/2 | Active, not recruiting --> Terminated; This study required dose reductions to the lower dose level (Dose level -1). But this dose level (Dose level -1) was not further explored because of lack of funding.

This study is an initial demonstration that the combination of PAC-1 and entrectinib may warrant further clinical investigation. Clinical trial registration: Clinical Trials.gov: NCT04589832.

Procaspase-3 (PC-3) is overexpressed in various tumor types, including gliomas. The maximum tolerated dose was not reached. Further dose escalation of PAC-1 in combination with TMZ is advised before conducting a formal prospective efficacy study in this patient population.

Cytarabine, FH535, and procaspase-activating compound-1 were estimated as reasonable chemotherapy options for patients in the high-risk group, whereas two taxanes and five tyrosine kinase inhibitors, including etoposide and vinorelbine, had therapeutic significance for patients in the low-risk group...The lymph node metastasis-related predictive signature based on TEKT2 and RPGR showed good performance in predicting the survival outcomes of patients with cervical cancer. The risk score of the predictive signature was related to genetic variation and immune infiltration, which could guide immunotherapy and chemotherapy strategies.

The activation factors procaspase-activating compound 1 (PAC-1) and P-selectin (CD62P), AP aggregation function, inflammation levels (interleukin 1 beta [IL-1β], interleukin 6 [IL-6], tumor necrosis factor alpha [TNF-α] and NOD-like receptor thermal protein domain associated protein 3 [NLRP3]), and autophagy-related genes (p62) during AP preservation were assessed...In conclusion, during AP preservation, inflammation, autophagy, and activation of immune cells were observed to increase. AP preservation time, IL-6, p62, and Beclin 1 were independent risk factors for PTR.

P1, N=18, Terminated, Vanquish Oncology, Inc. | Suspended --> Terminated; Business Reasons

Overall, we suggest that these hub genes can be used as biomarkers and novel targets for GC. FBN1 may be associated with drug resistance in gastric cancer.

PAC-1 dose at 750 mg/day was recommended for phase 2 studies. Activity of PAC-1 in treatment-refractory NET warrants further investigation.

We show that imatinib combined with PAC-1 work synergistically to inhibit proliferation and induce apoptosis in the treatment of GIST-T1 and GIST-882 cells. These findings provide preclinical evidence for future clinical trials in GIST treatment.

Especially, six compounds, including 4f-h and 4n-p, exhibited cytotoxicity equal or superior to positive control PAC-1, the first procaspase-3 activating compound...Analysis of compounds effects on cell cycle and apoptosis demonstrated that the representative compounds 4f, 4h, 4n, 4o and 4p (especially 4o) accumulated U937 cells in S phase and substantially induced late cellular apoptosis. The results show that compound 4o would serve as a template for further design and development of novel anticancer agents.

Compound 5e has emerged as a potential hit for further design and development of caspases activators and anticancer agents.

The most potent compound 5l displayed cytotoxicity up to 213-fold more potent than 5-fluorouracil and 87-fold more potent than PAC-1, the first procaspase-activating compound. Further docking simulation also revealed that this compound may be a potent allosteric inhibitor of procaspase-3 through chelation of the inhibitory zinc ion. Physicochemical and ADMET calculations for 5l provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent.

Our results suggest PAC-1 + TMZ as a potentially efficacious combination for the treatment of human meningioma, and also demonstrate the utility of including pet dogs with meningioma as a means to assess anticancer strategies for this common brain tumor.

This combination showed rapid kinetics of apoptosis induction as determined by caspase-3 activity, and strongly synergistic killing of both KGN as well as patient samples of primary and recurrent AGCT. We have demonstrated that the novel combination of two pro-apoptotic agents, TRAIL and PAC-1, significantly amplified the induction of apoptosis in AGCT cells, warranting further investigation of this combination as a potential therapy for AGCT.

Single agent PAC-1 is well tolerated and 750 mg was determined to be safe and recommended for phase 2 studies. Intriguing activity of PAC-1 was seen in all patients with NET refractory to standard therapies that warrants further investigation in phase 2 clinical setting.