caspase-9

Q-VD-OPH (Quinoline-Val-Asp-Difluorophenoxymethylketone) is a pan-caspase inhibitor with potent antiapoptotic properties.

Duocarmycin A, an antitumor antibiotic, is a DNA alkylator and efficiently alkylates adenine N3 at the 3′ end of AT-rich sequences in the DNA. Duocarmycin A, as a chemotherapeutic agent, results in HLC-2 cells typically apoptotic changes.

Caspase-9 Inhibitor III (Ac-LEHD-cmk), a caspase-9 inhibitor, demonstrates protective effects against ischemia-reperfusion-induced myocardial injury.

EF24 (3,5-Bis[(2-fluorophenyl)Methylene]-4-piperidinone) treatment increases the levels of activated caspase 3 and 9, and decreases the phosphorylated forms of MEK1 and ERK. EF24 shows potent anti-tumor activity in oral squamous cell carcinoma (OSCC) via deactivation of the MAPK ERK signaling pathway.

2-methoxycinnamaldehyde is a natural compound of Cinnamomum cassia,has been widely studied with regard to its antitumor activity.

Fenbufen (Lederfen) is a non-steroidal anti-inflammatory drug used primarily to treat inflammation in osteoarthritis, ankylosing spondylitis, and tendinitis. It can also be used to relieve backaches, sprains, and fractures. Fenbufen is available as a capsule or tablet sold with the brand names Cepal, Cinopal, Cybufen, Lederfen, and Reugast. Fenbufen acts by preventing cyclooxygenase from producing prostaglandins which can cause inflammation.

NS3694 is an inhibitor of apoptosis and inhibits apoptosome formation and caspase activation.

Fraxetin (7,8-dihydroxy-6-methoxy coumarin) has dual-antioxidative ,hepatoprotective and antihyperglycemic functions, it shows potent protective effects against CCl4 induced oxidative stress and hepatic fibrosis, has a marked inhibitory effect on S.aureus proliferation. It increased the level of Nrf2 ARE, and HO-1, inhibit the formation of ROS, cytochrome c release, activation of caspase-3 and 9, and suppressed the up-regulation of Bax.

Caspase-3 Inhibitor I (N-acetyl-asp-glu-val-asp-al) is a specific inhibitor of Caspase-3.

Procyanidin C1 is a natural polyphenol that causes DNA damage, cell cycle arrest, and apoptosis induction. It reduces Bcl-2 protein levels and enhances the expression of BAX, caspase 3, and 9 in cancer cells.

NLRP3-IN-9 (INF-4E) is an inhibitor of NLRP3 ATPase and caspase-1. NLRP3-IN-9 acts by irreversibly trapping thiol nucleophiles, which prevents both ATP- and nigericin-triggered pyroptosis of human THP-1 cells in a time- and concentration-dependent manner.

ML-9 suppresses MLCK, PKA, and PKC activity with Ki values of 4, 32, and 54 μM, respectively. ML-9 is a selective and effective inhibitor of Akt kinase, inhibits myosin light-chain kinase (MLCK), and stromal interaction molecule 1 (STIM1) activity. ML-9 causes autophagy by stimulating autophagosome formation and inhibiting their degradation.

Embelin (Embelic acid), isolated from the Japanese Ardisia herb, is an inhibitor of the X-linked inhibitor of apoptosis (IC50: 4.1 uM).

Talabostat (PT100, Val-boroPro) is a potent, nonselective and orally available dipeptidyl peptidase IV (DPP-IV) inhibitor with a Ki of 0.18 nM. Talabostat is a nonselective DPP-IV inhibitor, inhibiting DPP8 9, FAP, DPP2 and some other DASH family enzymes essentially as potently as it inhibits DPP-IV[1]. Talabostat stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and macrophages known as pyroptosis. The inhibition of two serine proteases, DPP8 and DPP9, activates the proprotein form of caspase-1 independent of the inflammasome adaptor ASC[2]. Talabostat competitively inhibits the dipeptidyl peptidase (DPP) activity of FAP and CD26 DPP-IV, and there is a high-affinity interaction with the catalytic site due to the formation of a complex between Ser630 624 and the boron of talabostat[3]. Talabostat can stimulate immune responses against tumors involving both the innate and adaptive branches of the immune system. In WEHI 164 fibrosarcoma and EL4 and A20 2J lymphoma models, PT-100 causes regression and rejection of tumors. The antitumor effect appears to involve tumor-specific CTL and protective immunological memory. Talabostat treatment of WEHI 164-inoculated mice increases mRNA expression of cytokines and chemokines known to promote T-cell priming and chemoattraction of T cells and innate effector cells[3]. Talabostat treated mice show significant less fibrosis and FAP expression is reduced. Upon PT100 treatment, significant differences in the MMP-12, MIP-1α, and MCP-3 mRNA expression levels in the lungs are also observed. Treatment with PT100 in this murine model of pulmonary fibrosis has an anti-fibro-proliferative effect and increases macrophage activation[4]. [1]. Connolly BA, et al. Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potencyand in vivo efficacy and safety. J Med Chem. 2008 Oct 9;51(19):6005-13. [2]. Okondo MC, et al. DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis. Nat Chem Biol. 2017 Jan;13(1):46-53. [3]. Adams S, et al. PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 2004 Aug 1;64(15):5471-80. [4]. Egger C, et al. Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis. Eur J Pharmacol. 2017 Aug 15;809:64-72.

ExcisaninA may be a potent inhibitor of AKT signaling pathway in tumor cells, it can inhibit invasion by suppressing MMP-2 and MMP-9 expression, it may be a potential anti-metastatic chemotherapeutic agent for the treatment of breast cancer. Excisanin A shows comparable inhibitory effects on the LPS-induced production of NO and PGE2, and activation of NF-kappaB without affecting cell viability.Excisanin A induces apoptosis in colon cancer cell line SW620 as determined by Annexin V staining, the cleavage of caspase-3 and the proteolytic degradation of poly (ADP-ribose) polymerase (PARP).

TC11 (1H-Isoindole-1,3(2H)-dione, 5-amino-2-[2,6-bis(1-methylethyl)phenyl]-TC11) is a potent inhibitor of tumor cell proliferation and an inducer of apoptosis via activation of caspase-3, 8 and 9.

Z-AEVD-FMK (Z-Ala-Glu-Val-Asp-Fluoromethyl Ketone) is a degradable ADC linker and caspase-10 inhibitor, reducing TNF-α butyrate-induced apoptosis, and inhibiting Gal-9-induced apoptosis.

Z-VAD is a competitive, irreversible, and broad-spectrum caspase inhibitor that inhibits all caspases except caspase-2, against which it is less effective. This compound reduces radiation-induced apoptosis and can induce autophagy and necrosis in radiation-treated xenografts of MDA-MB-231 and H460 in mice. When combined with radiation, Z-VAD significantly delays tumor growth and exhibits substantial anti-angiogenic effects in cancer xenografts.

Nemorosone is a polycyclic polyprenylated acylphloroglucinol (PPAP) originally isolated from C. rosea that has antiproliferative properties.1 Nemorosone inhibits growth of NB69, Kelly, SK-N-AS, and LAN-1 neuroblastoma cells (IC50s = 3.1-6.3 μM), including several drug-resistant clones, but not MRC-5 human embryonic fibroblasts (IC50 = >40 μM).2 It increases DNA fragmentation in LAN-1 cells in a dose-dependent manner, and decreases N-Myc protein levels and phosphorylation of ERK1/2 by MEK1/2. Nemorosone also inhibits growth of Capan-1, AsPC-1, and MIA-PaCa-2 pancreatic cancer cells (IC50s = 4.5-5.0 μM following a 72-hour treatment) but not human dermal and foreskin fibroblasts (IC50s = >35 μM).1 It induces apoptosis, abolishes the mitochondrial membrane potential, and increases cytosolic calcium concentration in pancreatic cancer cells in a dose-dependent manner. Nemorosone activates the caspase cascade in a dose-dependent manner and inhibits cell cycle progression, increasing the proportion of cells in the G0/G1 phase, in both neuroblastoma and pancreatic cancer cells.1,2 Nemorosone (50 mg/kg, i.p., per day) also reduces tumor growth in an MIA-PaCa-2 mouse xenograft model.3References1. Holtrup, F., Bauer, A., Fellenberg, K., et al. Microarray analysis of nemorosone-induced cytotoxic effects on pancreatic cancer cells reveals activation of the unfolded protein response (UPR). Br. J. Pharmacol. 162(5), 1045-1059 (2011).2. Díaz-Carballo, D., Malak, S., Bardenheuer, W., et al. Cytotoxic activity of nemorosone in neuroblastoma cells. J. Cell. Mol. Med. 12(6B), 2598-2608 (2008).3. Wold, R.J., Hilger, R.A., Hoheisel, J.D., et al. In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts. PLoS One 8(9), e74555 (2013). Nemorosone is a polycyclic polyprenylated acylphloroglucinol (PPAP) originally isolated from C. rosea that has antiproliferative properties.1 Nemorosone inhibits growth of NB69, Kelly, SK-N-AS, and LAN-1 neuroblastoma cells (IC50s = 3.1-6.3 μM), including several drug-resistant clones, but not MRC-5 human embryonic fibroblasts (IC50 = >40 μM).2 It increases DNA fragmentation in LAN-1 cells in a dose-dependent manner, and decreases N-Myc protein levels and phosphorylation of ERK1/2 by MEK1/2. Nemorosone also inhibits growth of Capan-1, AsPC-1, and MIA-PaCa-2 pancreatic cancer cells (IC50s = 4.5-5.0 μM following a 72-hour treatment) but not human dermal and foreskin fibroblasts (IC50s = >35 μM).1 It induces apoptosis, abolishes the mitochondrial membrane potential, and increases cytosolic calcium concentration in pancreatic cancer cells in a dose-dependent manner. Nemorosone activates the caspase cascade in a dose-dependent manner and inhibits cell cycle progression, increasing the proportion of cells in the G0/G1 phase, in both neuroblastoma and pancreatic cancer cells.1,2 Nemorosone (50 mg/kg, i.p., per day) also reduces tumor growth in an MIA-PaCa-2 mouse xenograft model.3 References1. Holtrup, F., Bauer, A., Fellenberg, K., et al. Microarray analysis of nemorosone-induced cytotoxic effects on pancreatic cancer cells reveals activation of the unfolded protein response (UPR). Br. J. Pharmacol. 162(5), 1045-1059 (2011).2. Díaz-Carballo, D., Malak, S., Bardenheuer, W., et al. Cytotoxic activity of nemorosone in neuroblastoma cells. J. Cell. Mol. Med. 12(6B), 2598-2608 (2008).3. Wold, R.J., Hilger, R.A., Hoheisel, J.D., et al. In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts. PLoS One 8(9), e74555 (2013).

Ac-AAVALLPAVLLALLAP-LEHD-CHO is a caspase inhibitor targeting caspases 4, 5, and 9, demonstrating protective effects in MCF-7 cells treated with Neocarzinostatin [1].

Ganoderic acid T1, a deacetylated derivative of Ganoderic acid T, diminishes mitochondrial membrane potential and triggers cell apoptosis by activating caspase-9 and caspase-3, thus impairing the antioxidant defense system of cancer cells. Additionally, it elevates intracellular ROS levels, yielding pro-oxidant activities and cytotoxicity [1].

CTL-12, a fatty acid synthase (FASN) inhibitor (IC50: 2.5 μM), induces apoptosis and disrupts the cell cycle at the Sub-G1 S phase. It upregulates caspase-9 and the apoptosis marker Bax, while downregulating the anti-apoptotic marker Bcl-xL. By inhibiting de novo lipogenesis, CTL-12 thwarts tumor cells' metabolic requirements and is frequently employed in breast and colorectal cancer studies [1].

Lucidenic acid B (Lucidenicacid B), a natural compound extracted from Ganoderma lucidum, induces activation of caspase-9 and caspase-3 and cleavage of PARP, which can induce apoptosis in human leukemia cells through mitochondrial mediation. Lucidenic acid B inhibits PMA-induced invasion of human hepatocellular carcinoma cells by inactivating the MAPK ERK signaling pathway and decreasing the binding activity of NF-kappaB and AP-1. Lucidenic acid B had no effect on cell cycle and necrotic cells.

NL13, a Polo-like kinase 4 (PLK4) inhibitor, exhibits an IC 50 value of 2.32 μM. It demonstrates the ability to suppress the viability of PC3 and DU145 prostate cancer cells with respective IC 50 values of 3.51 μM and 2.53 μM. NL13 also inhibits tumor growth in prostate cancer mice. Additionally, it deactivates the AKT signaling pathway by reducing CCNB1 CDK1 levels, leading to G2 M cell cycle arrest and initiating apoptosis through caspase-9 caspase-3 cleavage.