315183-21-2

Usage

Uses

Used in Cancer Treatment:
PAC-1 is used as a procaspase-3 activator for inducing apoptosis in a variety of cancer cell lines. Its mechanism of activation involves sequestering inhibitory zinc ions, allowing procaspase-3 to autoactivate. This process leads to the initiation of apoptosis, which is the programmed cell death that can help in the treatment of cancer.
Used in Enhancing Chemotherapy Efficacy:
PAC-1 is used as a sensitizer for cancer cells to various chemotherapeutic agents. By sensitizing cancer cells, PAC-1 can enhance the effectiveness of chemotherapy treatments, making them more efficient in targeting and eliminating cancer cells.
Used in Pharmaceutical Research:
PAC-1 is used as a research tool in the development of new cancer treatments and therapies. Its ability to activate procaspase-3 and induce apoptosis makes it a valuable compound for studying the mechanisms of cell death and the potential for new therapeutic interventions in cancer treatment.

Biological Activity

Procaspase-activating compound; activates procaspase-3 to produce caspase-3 (EC 50 = 0.22 μ M). Also activates procaspase-7 in a less efficient manner (EC 50 = 4.5 μ M). Pro-apoptotic; induces apoptosis in both cancerous and non-cancerous cells dependent on procaspase-3 concentration (IC 50 values are 0.003-1.41 and 5.02-9.98 μ M respectively).

References

1) Putt et al. (2006), Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy; Nat. Chem. Biol., 2 543 2) Peterson et al. (2009), PAC-1 activates procaspase-3 in vitro through relief of zinc-mediated inhibition; J. Mol. Biol., 388 144 3) Bolham et al. (2016), Small-Molecule Procaspase-3 Activation Sensitizes Cancer to Treatment with diverse Chemotherapeutics; ACS Cent. Sci., 2 545

InChI:InChI=1/C23H28N4O2/c1-2-7-20-10-6-11-21(23(20)29)16-24-25-22(28)18-27-14-12-26(13-15-27)17-19-8-4-3-5-9-19/h2-6,8-11,16,29H,1,7,12-15,17-18H2,(H,25,28)/b24-16+

Upstream product

• 90-02-8 salicylaldehyde 
• 28752-82-1 2-(allyloxy)benzaldehyde 
• 40004-08-8 1-(Ethoxycarbonylmethyl)piperazine 
• 100-44-7 benzyl chloride 
• 23173-76-4 ethyl 2-(4-benzylpiperazin-1-yl)acetate 
• 24019-66-7 3-allylsalicylaldehyde 
• 24632-70-0 2-(4-benzylpiperazin-1-yl)acetohydrazide 

Downstream Products

• 1075725-67-5 N'-(3-allyl-2-hydroxybenzyl)-2-(4-benzylpiperazin-1-yl)acetohydrazide 

Relevant academic research and scientific papers

Removal of metabolic liabilities enables development of derivatives of procaspase-activating compound 1 (PAC-1) with improved pharmacokinetics

Procaspase-activating compound 1 (PAC-1) is an o-hydroxy-N-acylhydrazone that induces apoptosis in cancer cells by chelation of labile inhibitory zinc from procaspase-3. PAC-1 has been assessed in a wide variety of cell culture experiments and in vivo models of cancer, with promising results, and a phase 1 clinical trial in cancer patients has been initiated (NCT02355535). For certain applications, however, the in vivo half-life of PAC-1 could be limiting. Thus, with the goal of developing a compound with enhanced metabolic stability, a series of PAC-1 analogues were designed containing modifications that systematically block sites of metabolic vulnerability. Evaluation of the library of compounds identified four potentially superior candidates with comparable anticancer activity in cell culture, enhanced metabolic stability in liver microsomes, and improved tolerability in mice. In head-to-head experiments with PAC-1, pharmacokinetic evaluation in mice demonstrated extended elimination half-lives and greater area under the curve values for each of the four compounds, suggesting them as promising candidates for further development.

Parallel synthesis and biological evaluation of 837 analogues of procaspase-activating compound 1 (PAC-1)

Procaspase-Activating Compound 1 (PAC-1) is an ortho-hydroxy N-acyl hydrazone that enhances the enzymatic activity of procaspase-3 in vitro and induces apoptosis in cancer cells. An analogue of PAC-1, called S-PAC-1, was evaluated in a veterinary clinical trial in pet dogs with lymphoma and found to have considerable potential as an anticancer agent. With the goal of identifying more potent compounds in this promising class of experimental therapeutics, a combinatorial library based on PAC-1 was created, and the compounds were evaluated for their ability to induce death of cancer cells in culture. For library construction, 31 hydrazides were condensed in parallel with 27 aldehydes to create 837 PAC-1 analogues, with an average purity of 91%. The compounds were evaluated for their ability to induce apoptosis in cancer cells, and through this work, six compounds were discovered to be substantially more potent than PAC-1 and S-PAC-1. These six hits were further evaluated for their ability to relieve zinc-mediated inhibition of procaspase-3 in vitro. In general, the newly identified hit compounds are two- to four-fold more potent than PAC-1 and S-PAC-1 in cell culture, and thus have promise as experimental therapeutics for treatment of the many cancers that have elevated expression levels of procaspase-3.

DESIGN, SYNTHESIS AND EVALUATION OF PROCASPASE ACTIVATING COMPOUNDS AS PERSONALIZED ANTI-CANCER DRUGS

Compositions and methods are disclosed in embodiments relating to induction of cell death such as in cancer cells. Compounds and related methods for synthesis and use thereof, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells are disclosed. Compounds are disclosed that have lower neurotoxicity effects than other compounds.

COMPOSITIONS AND METHODS INCLUDING CELL DEATH INDUCERS AND PROCASPASE ACTIVATION

Compositions and methods are disclosed in embodiments relating to induction of cell death such as in cancer cells. Compounds and related methods for synthesis and use thereof, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells are disclosed. Compounds are disclosed in connection with modification of procaspases such as procaspase-3. In embodiments, compositions are capable of activation of procaspase-3.