caspase-independent

Ubiquitin Isopeptidase Inhibitor I, G5 is a caspase-independent inducer of cell necrosis that induces cell death via the death receptor pathway (IC50 of 1.76 and 1.6 μM in E1A and E1A/C9DN cells, respectively).

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.

Kuguaglycoside C induces caspase-independent cell death, and is involved, at least in part, in the mechanism underlying cell necroptosis.

PB28 is a cyclohexylpiperazine derivative that functions as a potent and highly selective agonist of the sigma 2 (σ2) receptor, exhibiting a Ki (binding affinity) of 0.68 nM. At the same time, PB28 acts as an antagonist of the sigma 1 (σ1) receptor, with a Ki of 0.38 nM. PB28 demonstrates a lower affinity for other receptors. It effectively inhibits electrically evoked twitch in both the guinea pig bladder (EC50 value of 2.62 μM) and ileum (EC50 value of 3.96 μM). Moreover, PB28 exhibits the ability to modulate protein-protein interaction between SARS-CoV-2 and human cells. Additionally, PB28 triggers caspase-independent apoptosis and possesses significant antitumor activity.

CIL62 is a caspase-3/7-independent inducer of cell death. The mechanism of action of CIL62 is Necrostatin-1 dependent cell death [1].

Regiolone demonstrates phytotoxicity. Regiolone also has anti-proliferative and apoptotic activities, it can induce apoptosis in MCF-7 cells through the caspase-3 independent pathway.

Phenoxodiol (Idronoxil) activates the mitochondrial caspase system, inhibits X-linked inhibitor of apoptosis(XIAP), disrupts FLICE inhibitory protein(FLIP) expression, and sensitizes the cancer cells to Fas-mediated apoptosis. Phenoxodiol induces cell cycle arrest in the G1/S phase of the cell cycle and upregulates p21WAF1 via a p53 independent manner. Phenoxodiol also inhibits DNA topoisomerase II.

Triphen Diol, a phenol diol derivative, exhibits potent anticancer properties against pancreatic cancer and cholangiocarcinoma, efficiently inducing pancreatic cell apoptosis via both caspase-mediated and caspase-independent mechanisms.

AVN-944 (VX-944)(VX-944) is a selective, noncompetitive inhibitor of human IMPDH with Ki of 6-10 nM for IMPDH1/IMPDH2.

Thiobenzanilide 63T is a small molecule that selectively induces cancer cell death in a caspase-independent pathway,

7-bromoindirubin-3'-oxime (7BIO) is a caspase independent nonapoptotic cell death inducer. 7BIO is an inhibitor of FLT3, DYRK1A, DYRK2, Aurora B and Aurora C kinases.

15-Acetoxyscirpenol, a member of the acetoxyscirpenol moiety mycotoxins (ASMs), potently induces apoptosis and inhibits the growth of Jurkat T cells in a dose-dependent manner. This effect is mediated through the activation of caspases independent of caspase-3[1].

ALC67 has a promising anticancer activity that results in the recent discovery of a series of 3-propionyl thiazolidine-4-carboxylic acid ethyl esters as a family of novel antiproliferative agents. It is an activator of the caspase-9 involved apoptotic pat