bortezomib

Bortezomib (LDP 341) 是一种 20S 蛋白酶体抑制剂 (Ki=0.6 nM)，具有可逆性和选择性。Bortezomib 具有抗肿瘤活性，可以抑制 NF-κB，可破坏细胞周期、诱导细胞凋亡。

(1S,2S)-Bortezomib (Bortezomib) 是 Bortezomib 的对映异构体。 Bortezomib 是一种可逆的选择性蛋白酶体抑制剂，对 20S 蛋白酶体的 Ki 为 0.6 nM。

CASIN (Pirl1-related Compound 2) 是选择性GTPase Cdc42抑制剂，IC50值是 2 uM。

Compound 13 (Bortezomibanalog) 是一种Bortezomib的类似物，作为20S蛋白酶体亚基β5配体的活性对照。

Bortezomib-pinanediol 是一种蛋白酶体抑制剂。是硼替佐米的前药。

LCS-1 是一种选择性超氧化物歧化酶 1 (SOD1) 抑制剂，也是吡哒嗪-3-酮衍生物，在高浓度时显示出锥虫杀灭活性。LCS-1 抑制超氧化物歧化酶 1 诱导神经胶质瘤细胞的 ROS 依赖性死亡并降解 PARP 和 BRCA1。

2,5-Dihydroxyacetophenone (Quinacetophenone) 是从熟地黄中分离出的一种天然产物，通过阻断 ERK1 2和 NF-κB 信号通路，抑制活化巨噬细胞中炎症介质的产生。

PROTAC 20S proteasomesubunit β5 degrader 1 (compound 12f)，一种针对20S蛋白酶体亚基β5的靶向降解剂，在FaDu细胞中表现出0.11 μM的DC50值。此化合物能在FaDu和KM3 BTZ细胞中干扰细胞周期，促进细胞凋亡(apoptosis)，并有效抑制细胞的增殖与迁移。此外，PROTAC 20S proteasomesubunit β5 degrader 1 还可用于研究咽癌和多发性骨髓瘤中对Bortezomib的耐药性。

HCI-2184 is an inhibitor of AXL kinase and Nek2 that acts by successfully mitigating drug resistance in bortezomib-resistant multiple myeloma.

NR-160 is an inhibitor of histone deacetylase 6 (HDAC6; IC50= 0.03 μM).1It is selective for HDAC6 over HDAC1, -2, -3, -4, and -8 (IC50s = 5.18, 2.26, 8.48, 55.4, and 14.7 μM, respectively). NR-160 is cytotoxic against a panel of seven cancer cell lines (IC50s = 22.5-51.8 μM). It enhances cytotoxicity induced by bortezomib in HL-60 cells, as well as cytotoxicity induced by epirubicin or daunorubicin in CCRF-HSB-2 T cell acute lymphoblastic leukemia cells.

Selective, ATP-competitive p38 inhibitor (IC50 = 9 nM for p38α in vitro). Displays approximately 10-fold selectivity for p38α over p38β and 2000-fold selectivity for p38α over 20 other kinases. Reduces p38α phosphorylation in multiple myeloma cells in vitro and in vivo; activity results in decreased tumor burden and angiogenesis in murine models of multiple myeloma. Also enhances bortezomib-induced cytotoxicity against multiple myeloma cells. Hideshima et al (2004) p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene. 23 8766 PMID:15480425 |Giafis et al (2006) Role of the p38 mitogen-activated protein kinase pathway in the generation of arsenic trioxide-dependent cellular responses. Cancer Res. 66 6763 PMID:16818652 |Vanderkerken et al (2007) Inhibition of p38α mitogen-activated protein kinase prevents the development of osteolytic bone disease, reduces tumor burden, and increases survival in murine models of multiple myeloma. Cancer Res. 67 4572 PMID:17495322

INCB16562 is a novel, selective, and orally bioavailable small-molecule inhibitor of JAK1 and JAK2 markedly selective over JAK3. Treatment of myeloma cells with INCB16562 potently inhibited interleukin-6 (IL-6)-induced phosphorylation of STAT3. INCB16562 abrogated the protective effects of recombinant cytokines or bone marrow stromal cells and sensitized myeloma cells to cell death by exposure to dexamethasone, melphalan, or bortezomib. Oral administration of INCB16562 antagonized the growth of myeloma xenografts in mice and enhanced the antitumor activity of relevant agents in combination studies. INCB16562 is a potent JAK1 2 inhibitor and that mitigation of JAK STAT signaling by targeting JAK1 and JAK2 will be beneficial in the treatment of myeloma patients, particularly in combination with other agents. ( source: Neoplasia. 2010 Jan;12(1):28-38. ).

CEP-18770 is an orally bioavailable synthetic P2 threonine boronic acid inhibitor of the chymotrypsin-like activity of the proteasome, with potential antineoplastic activity. Proteasome inhibitor CEP 18770 represses the proteasomal degradation of a variety of proteins, including inhibitory kappaBalpha (IkappaBalpha), resulting in the cytoplasmic sequestration of the transcription factor NF-kappaB; inhibition of NF-kappaB nuclear translocation and transcriptional up-regulation of a variety of cell growth-promoting factors; and apoptotic cell death in susceptible tumor cell populations. In vitro studies indicate that this agent exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells relative to the proteasome inhibitor bortezomib. The intracellular protein IkappaBalpha functions as a primary inhibitor of the proinflammatory transcription factor NF-kappaB.

Ixazomib citrate, also known as MLN9708, is a prodrug of Ixazomib (MMLN-2238). MLN9708 is an orally bioavailable second generation proteasome inhibitor (PI) with potential antineoplastic activity. MLN9708, after hydrolyzing to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity. MLN9708, compared with bortezomib, has improved pharmacokinetics, pharmacodynamics, and antitumor activity in preclinical studies.