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Home >> Signaling Pathways >> Apoptosis

Apoptosis(凋亡)

As one of the cellular death mechanisms, apoptosis, also known as programmed cell death, can be defined as the process of a proper death of any cell under certain or necessary conditions. Apoptosis is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body.

Many biochemical events and a series of morphological changes occur at the early stage and increasingly continue till the end of apoptosis process. Morphological event cascade including cytoplasmic filament aggregation, nuclear condensation, cellular fragmentation, and plasma membrane blebbing finally results in the formation of apoptotic bodies. Several biochemical changes such as protein modifications/degradations, DNA and chromatin deteriorations, and synthesis of cell surface markers form morphological process during apoptosis.

Apoptosis can be stimulated by two different pathways: (1) intrinsic pathway (or mitochondria pathway) that mainly occurs via release of cytochrome c from the mitochondria and (2) extrinsic pathway when Fas death receptor is activated by a signal coming from the outside of the cell.

Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis.

Caspase family comprises conserved cysteine aspartic-specific proteases, and members of caspase family are considerably crucial in the regulation of apoptosis. There are 14 different caspases in mammals, and they are basically classified as the initiators including caspase-2, -8, -9, and -10; and the effectors including caspase-3, -6, -7, and -14; and also the cytokine activators including caspase-1, -4, -5, -11, -12, and -13. In vertebrates, caspase-dependent apoptosis occurs through two main interconnected pathways which are intrinsic and extrinsic pathways. The intrinsic or mitochondrial apoptosis pathway can be activated through various cellular stresses that lead to cytochrome c release from the mitochondria and the formation of the apoptosome, comprised of APAF1, cytochrome c, ATP, and caspase-9, resulting in the activation of caspase-9. Active caspase-9 then initiates apoptosis by cleaving and thereby activating executioner caspases. The extrinsic apoptosis pathway is activated through the binding of a ligand to a death receptor, which in turn leads, with the help of the adapter proteins (FADD/TRADD), to recruitment, dimerization, and activation of caspase-8 (or 10). Active caspase-8 (or 10) then either initiates apoptosis directly by cleaving and thereby activating executioner caspase (-3, -6, -7), or activates the intrinsic apoptotic pathway through cleavage of BID to induce efficient cell death. In a heat shock-induced death, caspase-2 induces apoptosis via cleavage of Bid.

Bcl-2 family members are divided into three subfamilies including (i) pro-survival subfamily members (Bcl-2, Bcl-xl, Bcl-W, MCL1, and BFL1/A1), (ii) BH3-only subfamily members (Bad, Bim, Noxa, and Puma9), and (iii) pro-apoptotic mediator subfamily members (Bax and Bak). Following activation of the intrinsic pathway by cellular stress, pro‑apoptotic BCL‑2 homology 3 (BH3)‑only proteins inhibit the anti‑apoptotic proteins Bcl‑2, Bcl-xl, Bcl‑W and MCL1. The subsequent activation and oligomerization of the Bak and Bax result in mitochondrial outer membrane permeabilization (MOMP). This results in the release of cytochrome c and SMAC from the mitochondria. Cytochrome c forms a complex with caspase-9 and APAF1, which leads to the activation of caspase-9. Caspase-9 then activates caspase-3 and caspase-7, resulting in cell death. Inhibition of this process by anti‑apoptotic Bcl‑2 proteins occurs via sequestration of pro‑apoptotic proteins through binding to their BH3 motifs.

One of the most important ways of triggering apoptosis is mediated through death receptors (DRs), which are classified in TNF superfamily. There exist six DRs: DR1 (also called TNFR1); DR2 (also called Fas); DR3, to which VEGI binds; DR4 and DR5, to which TRAIL binds; and DR6, no ligand has yet been identified that binds to DR6. The induction of apoptosis by TNF ligands is initiated by binding to their specific DRs, such as TNFα/TNFR1, FasL /Fas (CD95, DR2), TRAIL (Apo2L)/DR4 (TRAIL-R1) or DR5 (TRAIL-R2). When TNF-α binds to TNFR1, it recruits a protein called TNFR-associated death domain (TRADD) through its death domain (DD). TRADD then recruits a protein called Fas-associated protein with death domain (FADD), which then sequentially activates caspase-8 and caspase-3, and thus apoptosis. Alternatively, TNF-α can activate mitochondria to sequentially release ROS, cytochrome c, and Bax, leading to activation of caspase-9 and caspase-3 and thus apoptosis. Some of the miRNAs can inhibit apoptosis by targeting the death-receptor pathway including miR-21, miR-24, and miR-200c.

p53 has the ability to activate intrinsic and extrinsic pathways of apoptosis by inducing transcription of several proteins like Puma, Bid, Bax, TRAIL-R2, and CD95.

Some inhibitors of apoptosis proteins (IAPs) can inhibit apoptosis indirectly (such as cIAP1/BIRC2, cIAP2/BIRC3) or inhibit caspase directly, such as XIAP/BIRC4 (inhibits caspase-3, -7, -9), and Bruce/BIRC6 (inhibits caspase-3, -6, -7, -8, -9). 

Any alterations or abnormalities occurring in apoptotic processes contribute to development of human diseases and malignancies especially cancer.

References:
1.Yağmur Kiraz, Aysun Adan, Melis Kartal Yandim, et al. Major apoptotic mechanisms and genes involved in apoptosis[J]. Tumor Biology, 2016, 37(7):8471.
2.Aggarwal B B, Gupta S C, Kim J H. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey.[J]. Blood, 2012, 119(3):651.
3.Ashkenazi A, Fairbrother W J, Leverson J D, et al. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors[J]. Nature Reviews Drug Discovery, 2017.
4.McIlwain D R, Berger T, Mak T W. Caspase functions in cell death and disease[J]. Cold Spring Harbor perspectives in biology, 2013, 5(4): a008656.
5.Ola M S, Nawaz M, Ahsan H. Role of Bcl-2 family proteins and caspases in the regulation of apoptosis[J]. Molecular and cellular biochemistry, 2011, 351(1-2): 41-58.

Products for  Apoptosis

  1. Cat.No. 产品名称 Information
  2. GC62716 MD-222 MD-222 是一种首创的高效的基于 PROTAC 的 MDM2 降解剂。MD-222 诱导 MDM2 蛋白快速降解并激活细胞中的野生型 p53。MD-222 具有抗癌作用。
  3. GC62707 Murizatoclax Murizatoclax (AMG 397) 是一种有效，选择性和具有口服活性的髓样白血病 1 (MCL-1) 抑制剂，Ki 值为 15 pM。Murizatoclax 与促凋亡 BCL-2 家族成员竞争性结合 MCL1 的 BH3 结合沟。Murizatoclax 可用于癌症的研究。
  4. GC62693 SCR130 SCR130 is a novel DNA repair inhibitor with IC50s of 14 μM in Reh cells and 2 μM in Nalm6 cells. SCR130 specifically inhibits DNA Ligase IV‐mediated joining with minimal or no effect on Ligase III and Ligase I mediated joining.
  5. GC62688 PD-1/PD-L1-IN-8

    INCB086550 (PD-1/PD-L1-IN-8) is potent a PD-1/PD-L1 inhibitor, with an IC50 <= 10 nM.
  6. GC62682 BMSpep-57 hydrochloride BMSpep-57 hydrochloride 是一种有效的大环肽类抑制剂，抑制 PD-1/PD-L1 相互作用，IC50 为 7.68 nM。BMSpep-57 hydrochloride 与 PD-L1 结合，MST 和 SPR 测定表明，Kd 分别为 19 nM 和 19.88 nM。BMSpep-57 hydrochloride 通过增加 PBMC 中 IL-2 的产生促进 T 细胞功能。
  7. GC62676 TJ191 TJ191 is a selective anti-cancer small molecule that targets low TβRIII-expressing malignant T-cell leukemia/lymphoma cells.
  8. GC62665 JAK2/FLT3-IN-1 TFA JAK2/FLT3-IN-1 (TFA) 是一种口服有效的双重 JAK2/FLT3 抑制剂，对 JAK2，FLT3，JAK1 和 JAK3 的 IC50 分别为 0.7 nM，4 nM，26 nM 和 39 nM。JAK2/FLT3-IN-1 (TFA) 具有抗癌活性。
  9. GC62658 PD-1/PD-L1-IN 7 PD-1/PD-L1-IN 7 (PD-1/PD-L1-IN 7) 是一种人 PD-1/PD-L1 蛋白/蛋白相互作用抑制剂，IC50 为 0.213 nM。
  10. GC62657 MRIA9 MRIA9 是 ATP 竞争性的、pan-SIK 和 PAK2/3 抑制剂，其对 SIK1、SIK2 和 SIK3 的 IC50 值分别为 516 nM, 180 nM 和 127 nM。
  11. GC62654 GSK778 GSK778 (iBET-BD1) is a strong BD1 bromodomain inhibitor of the BET proteins, with IC50 value of 75 nM for BRD2 BD1, 41 nM for BRD3 BD1, 41 nM for BRD4 BD1, and 143 nM for BRDT BD1.
  12. GC62652 UZH1a UZH1a 是一种有效和选择性的 METTL3 抑制剂，IC50 值为 280 nM。UZH1a 可用于细胞进程的转录组调控。UZH1a 具有抗肿瘤活性。UZH1a 也可用作研究 METTL3 的化学探针。
  13. GC62645 Fosifloxuridine nafalbenamide Fosifloxuridine nafalbenamide (NUC-3373) 属于嘧啶核苷酸类似物，是一种胸腺嘧啶合酶 (Thymidylate synthase) 抑制剂。Fosifloxuridine nafalbenamide 具有抗癌活性。Fosifloxuridine nafalbenamide 具有诱发宿主免疫反应和增强免疫治疗的潜力。
  14. GC62641 WEHI-9625 WEHI-9625 是一种首创的，三环砜小分子凋亡抑制剂，EC50 值为 69 nM。WEHI-9625 与 VDAC2 结合可促进其抑制小鼠 BAK 诱导的细胞凋亡的能力，但对人 BAK 和与凋亡效应密切相关的 BAX 因子均完全无效。
  15. GC62640 APG-1387 APG-1387 是一种二价 SMAC 模拟物，是 IAP 拮抗剂，可阻断 IAP 家族蛋白 (XIAP，cIAP-1，cIAP-2 和 ML-IAP) 的活性。APG-1387 诱导 cIAP-1 和 XIAP 蛋白降解以及 caspase-3 激活和 PARP 裂解，从而导致细胞凋亡。APG-1387 可用于肝细胞癌，卵巢癌和鼻咽癌的研究。
  16. GC62639 rel-Zotatifin reli -Zotatifin是Zotatifin的外消旋异构体，作为eIF4A抑制剂，活性小于Zotatifin。Zotatifin (eFT226) 是一种有效，选择性和耐受性良好的 eIF4A 抑制剂。Zotatifin 可促进 eIF4A 与 5’-UTRs 中具有识别基序的特定 mRNA 序列结合 (IC50=2 nM)，并干扰 eIF4F 起始复合物的组装。
  17. GC62633 GGTI-2154 GGTI-2154 是一种有效和选择性的 geranylgeranyltransferase I (GGTase I) 抑制剂，IC50 值为 21 nM。GGTI-2154 对 GGTase I 的选择性是 FTase (IC50=5600 nM) 的 200 倍以上。GGTI-2154 可用于癌症的研究。
  18. GC62630 TAS-117 hydrochloride TAS-117 hydrochloride 是一种有效、选择性、具有口服活性的别构 Akt 抑制剂 (对 Akt1、2 和 3 的 IC50 分别为 4.8、1.6 和 44 nM)。TAS-117 hydrochloride 激发抗骨髓瘤活性并增强蛋白酶体抑制诱导的致命内质网应激。TAS-117 hydrochloride 诱导细胞凋亡 (apoptosis) 和自噬 (autophagy)。
  19. GC62629 MB710 MB710 是一种氨基苯并噻唑衍生物，是致癌 p53 突变体 Y220C 的稳定剂。MB710 与 Y220C 紧密结合并稳定 p53-Y220C，Kd 值为 4?μM。 MB710 在 p53-Y220C 细胞系中显示抗癌活性。
  20. GC62626 ICCB-19 hydrochloride ICCB-19 hydrochloride is an inhibitor of TNFRSF1A Associated Via Death Domain (TRADD) with IC50 of 1.12 μM and 2.01 μM for protecting Velcade-induced apoptosis in Jurkat cells and protecting RDA in MEFs, respectively. ICCB-19 indirectly inhibits Receptor-interacting serine/threonine-protein kinase 1 (RIPK1). ICCB-19 effectively induces autophagy.
  21. GC62621 Milademetan tosylate hydrate Milademetan (DS-3032) tosylate hydrate 是特异性的、具有口服活性的 MDM2 抑制剂，用于急性髓系白血病和实体肿瘤的研究。Milademetan (DS-3032) tosylate hydrate 可诱导 G1 细胞周期阻滞、衰老和凋亡。
  22. GC62620 NHWD-870 NHWD-870 inhibits CSF1 expression through suppressing BRD4 and its target HIF1α.
  23. GC62615 AS-99 AS-99 是一流的、有效的、选择性的 ASH1L 组蛋白甲基转移酶抑制剂（IC50=0.79μ；M，Kd=0.89μ；M），具有抗白血病活性。 AS-99 阻断细胞增殖，诱导细胞凋亡和分化，下调 MLL 融合靶基因，并减少体内白血病负担。
  24. GC62599 BCL6-IN-4 BCL6-IN-4 是一种有效的 B 细胞淋巴瘤 6 (BCL6) 抑制剂，IC50IC50 为 97 nM。BCL6-IN-4 具有抗肿瘤活性。
  25. GC62598 MI-1061 TFA MI-1061 TFA 是一种有效的，口服可生物利用的，化学稳定性的 MDM2 (MDM2-p53 互作) 抑制剂 (IC50=4.4 nM; Ki=0.16 nM)。MI-1061 TFA 激活小鼠 SJSA-1 异种移植瘤组织中 p53 并诱导凋亡，具有抗肿瘤活性。
  26. GC62596 CDK7-IN-3 CDK7-IN-3 (CDK7-IN-3) 是一种具有口服活性的高选择性非共价 CDK7 抑制剂，KD 为 0.065 nM。 CDK7-IN-3 对 CDK2 (Ki=2600 nM)、CDK9 (Ki=960 nM)、CDK12 (Ki=870 nM) 显示出较差的抑制作用。 CDK7-IN-3 诱导肿瘤细胞凋亡并具有抗肿瘤活性。
  27. GC62594 hnRNPK-IN-1 hnRNPK-IN-1 是一种异质核糖核蛋白 K (hnRNPK) 结合配体，用 SPR 和 MST 测量的 Kd 值分别为 4.6 μM 和 2.6 μM。hnRNPK-IN-1 通过破坏 hnRNPK 和 c-myc 启动子的结合来抑制 c-myc 转录。hnRNPK-IN-1诱导 Hela 细胞凋亡 (apoptosis)，并具有很强的抗肿瘤活性。
  28. GC62590 E64FC26 E64FC26 是蛋白质二硫键异构酶 (PDI) 家族的一种有效的泛抑制剂，对 PDIA1、PDIA3、PDIA4、TXNDC5 和 PDIA6 的 IC50 分别为 1.9、20.9、25.9、16.3 和 25.4 μM。E64FC26 显示抗骨髓瘤活性。
  29. GC62567 Pralnacasan Pralnacasan (VX-740) 是一种有效的，选择性的，非肽型，具有口服活性白介素 1β 转化酶 (ICE, caspase 1) 抑制剂，Ki 为 1.4 nM。Pralnacasan 抑制促炎细胞因子 IL-18，IL-1β 和 IFN-γ。Pralnacasan 有潜力用于骨关节炎和类风湿关节炎的研究。
  30. GC62562 EGFR-IN-11 EGFR-IN-11 是第四代 EGFR-酪氨酸激酶抑制剂 (EGFR-TKI)，对三重突变的 EGFRL858R/T790M/C797S 的 IC50 为 18 nM。EGFR-IN-11 显著抑制 EGFR 磷酸化，诱导细胞凋亡，将细胞周期阻滞在 G0/G1处。
  31. GC62561 CCT369260 CCT369260 (compound 1) 是具有口服活性的、B 细胞淋巴瘤 6 (BCL6) 抑制剂，具有抗肿瘤活性，其 IC50 值为 520 nM。
  32. GC62558 WDR5-IN-1 WDR5-IN-1 是一种有效的选择性 WD 重复结构域 5 (WDR5) 抑制剂，Kd 为 <0.02 nM。WDR5-IN-1 抑制 MLL1 组蛋白甲基转移酶活性 (HMT)，IC50为 2.2 nM。WDR5-IN-1 减少 WDR5 移位基因的 MYC 募集，并在 CHP-134 (神经母细胞瘤) 和 Ramos (Burkitt淋巴瘤) 细胞系中显示出有效的抗增殖作用。
  33. GC62557 MDM2-IN-1 MDM2-IN-1 (Compound 30) 是一种合成的 MDM2-p53 相互作用 (MDM2) 抑制剂，包含反式 (D-)构型。
  34. GC62554 S65487 S65487 (VOB560) 是一种有效的选择性 Bcl-2 抑制剂。 S65487 对 BCL-2 突变也有活性，例如 G101V 和 D103Y。S65487 对 MCL-1，BFL-1 和 BCL-XL 的亲和力较差。S65487 诱导细胞凋亡 (apoptosis) 并具有抗癌活性。
  35. GC62536 Bromelain A mixture of proteolytic enzymes
  36. GC62528 (Rac)-Hesperetin (Rac)-Hesperetin 是Hesperetin 的外消旋体。 Hesperetin 是一种天然黄烷酮类物质，为有效的，广谱的人 UGT 抑制剂。Hesperetin 可通过激活 p38 MAPK 来诱导凋亡。
  37. GC62505 Pelcitoclax Pelcitoclax (APG-1252) 是一种有效的 Bcl-2/Bcl-xl 抑制剂，具有抗肿瘤和促凋亡作用。
  38. GC62502 PD-1/PD-L1-IN-NP19 A PD-1/PD-L1 interaction inhibitor
  39. GC62499 ATH686 ATH686 是一种有效的，选择性的，ATP 竞争性的 FLT3 抑制剂。ATH686 靶向突变 FLT3 蛋白激酶活性，并通过诱导凋亡 (apoptosis) 和抑制细胞周期来抑制具有 FLT3 突变的细胞的增殖。ATH686 具有抗白血病作用。
  40. GC62487 POMHEX POMHEX 是一个消旋混合物，是具有细胞渗透性的 HEX 的 POM 前体药物，是ENO2 的特异性抑制剂。POMHEX 对ENO1 缺失的细胞表现出低纳摩尔级别活性，并对 ENO1 缺失的肿瘤模型表现出良好的抗癌效果。POMHEX 是有效的糖酵解抑制剂。
  41. GC62483 Pomolic acid Pomolic acid is a pentacyclic triterpene isolated from Euscaphis japonica, and is highly effective in inhibiting cell growth and induces apoptosis.
  42. GC62478 ζ-Stat ζ-Stat (NSC37044) is a specific and atypical protein kinase Cζ (PKCζ) inhibitor, with an IC50 of 5 μM.
  43. GC62457 UZH1 UZH1 是 UZH1a 和 UZH1b 的外消旋体。UZH1a 是一种有效和选择性的 METTL3 抑制剂，IC50 值为 280 nM。UZH1b (IC50=28 µM) 基本无活性。UZH1 可用于细胞进程的转录组调控。UZH1 具有抗肿瘤活性。UZH1 也可用作研究 METTL3 的化学探针。
  44. GC62455 RIPK3-IN-1 RIPK3-IN-1 是 II 型 RIPK3 DFG-out 位点抑制剂，IC50 为 9.1 nM。RIPK3-IN-1 抑制 RIPK1 和 RIPK2，IC50 为 5.5 和 >10 μM。RIPK3-IN-1 还是 c-Met 激酶抑制剂，IC50 为 1.1 μM。
  45. GC62453 GZD856 formic GZD856 formic 是一种有效的和具有口服活性的 PDGFRα/β 抑制剂，IC50 值分别为 68.6 和 136.6 nM。GZD856 formic 也是 Bcr-AblT315I 的抑制剂，对天然 Bcr-Abl 和 T315I 突变型的 IC50 值分别为 19.9 和 15.4 nM。GZD856 formic 具有抗肿瘤活性。
  46. GC62451 Benpyrine Benpyrine 是一种高度特异性的具有口服活性的 TNF-α 抑制剂，KD 值为 82.1 μM。Benpyrine 与 TNF-α 紧密结合并阻断其与 TNFR1 的相互作用，IC50 值为 0.109 µM。Benpyrine 可用于 TNF-α 介导的炎症和自身免疫性疾病的研究。
  47. GC62444 SDZ 224-015 SDZ 224-015 是具有口服活性的、IL-1β 转化酶和 caspase-1 的抑制剂。SDZ 224-015 具有抗COVID-19的活性，靶向 Mpro (IC50 of 30 nM)。
  48. GC62442 Casein Kinase inhibitor A51 Casein Kinase inhibitor A51 是一种有效且具有口服活性的酪蛋白激酶 1α (CK1α) 抑制剂。Casein Kinase inhibitor A51 可诱导白血病细胞凋亡 (apoptosis)，并具有有效的抗白血病活性。
  49. GC62426 ASK1-IN-2 ASK1-IN-2 is a potent and orally active inhibitor of apoptosis signal-regulating kinase 1 (ASK1), with an IC50 of 32.8 nM.
  50. GC62419 Apcin-A Apcin-A，是 Apcin 衍生物，是一种后期促进复合物 (APC) 抑制剂。Apcin-A 与 Cdc20 强烈相互作用，抑制 Cdc20 底物的泛素化。Apcin-A 可用于合成 PROTAC CP5V 。
  51. GC62411 QTX125 QTX125 是一种有效且高度选择性的 HDAC6 抑制剂。与其他 HDAC 相比，QTX125 对 HDAC6 具有出色的选择性。QTX125 具有抗肿瘤作用。

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