caspase-independent

AVN-944 (VX-944) 是一种选择性的、非竞争性 IMPDH 抑制剂，对IMPDH1和IMPDH2的Ki=为6-10nM。

Ubiquitin Isopeptidase Inhibitor I, G5 是一种不依赖于 caspase 的细胞坏死诱导剂，通过死亡受体途径的诱导细胞死亡（在 E1A 和 E1A C9DN 细胞中的 IC50 分别为 1.76 和 1.6 μM）。

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.

CIL62 是一种不依赖 caspase-3 7 的细胞死亡诱导剂。CIL62的作用机制是 Necrostatin-1 依赖性细胞死亡。

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].

Phenoxodiol (Idronoxil) 是合成genestein 的类似物，激活线粒体caspase 系统，抑制XIAP，使癌细胞对fas 介导的凋亡敏感。它在细胞周期的G1 S 期诱导细胞周期阻滞，通过独立于p53的方式上调p21WAF1。它通过稳定可分裂复合物抑制DNA 拓扑异构酶II，从而阻止DNA 复制。

MAPK-IN-3 (Compound 4a) 是一种抗增殖剂，特别对 KYSE 30、HCT 116 和 HGC 27 具有强效抑制作用，其 IC50 分别为 0.57 μM、3.27 μM 和 2.28 μM。通过 p53 依赖机制，MAPK-IN-3 阻滞细胞周期，并通过 p53 非依赖机制诱导细胞凋亡。该化合物下调细胞周期相关蛋白（如 Cyclin D1 和 Cyclin B1）的表达，上调促凋亡蛋白（如裂解 PARP、裂解 caspase-7 和裂解 caspase-9）的表达，减少抗凋亡蛋白（如 Bcl-2）的表达，增加 KYSE 30 细胞内的 ROS 水平，并上调与 ROS 相关的 MAPK 信号通路成员（如 p-ERK、p-p38 和 p-JNK）的表达。

7BIO 是靛玉红的衍生物，抑制细胞周期蛋白依赖性激酶5 和糖原合酶激酶-3β。它抑制 Aβ 寡聚体诱导的神经炎症、突触损伤、tau 过度磷酸化、星形胶质细胞和小胶质细胞的活化，并减轻 Aβ 寡聚体诱导的小鼠认知障碍。

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

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

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.

Triphen diol 是一种苯酚二醇衍生物，对胰腺癌和胆管癌具有优异的抗癌活性，可以通过caspase 介导的和caspase 不依赖的两种机制诱导胰腺细胞凋亡(apoptosis)。

Anticanceragent 223 (Compound V-d) 是一款激发细胞死亡的化合物，作用机制包括依赖和不依赖半胱氨酸蛋白酶的路径。该化合物能有效抑制肿瘤球体的形成，并使原本对顺铂耐药的A2780细胞恢复对该药物的敏感性。

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

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.

NDI-Lyso 是一款针对溶酶体的肿瘤抑制剂。通过猫卵白酶 B 催化的 EISA 机制，在癌变溶酶体中形成坚硬的长纤维，进而引发溶酶体肿胀和膜透化（LMP），最终导致膜结构破坏，从而通过非经典的caspase非依赖性途径实现癌细胞的凋亡（Apoptosis）。此外，NDI-Lyso 在多种癌细胞类型以及耐药性癌细胞中显示出了高度的选择性抗癌活性（IC50 约为 10 μM），对正常细胞的毒性较低（IC50 > 60 μM）。