Venetoclax (ABT-199, GDC-0199) is a selective inhibitor of Bcl-2 with a K i of 0.01 nM in cell-free assays. Compared to Bcl-XL and Bcl-W more than 4800 times more selective, no inhibitory activity against McL-1[1].
ABT-199 cell killing was selective and mechanism dependent, BCL2high status is thus a potential predictive marker for sensitivity to ABT-199[1].BIM binding to BCL2 correlates with ABT-199 response and further showed that knockout of BIM results in decreased ABT-199 sensitivity. Eexpression of B-cell genes as enriched in ABT-199-sensitive myeloma, although no single gene consistently delineated sensitive and resistant cells[4]. In the ABT-199-resistant OCI-AML3 cell line, CXCL12 promoted an increase in the proportion of cells expressing high levels of embryonic stem cell core transcription factors abrogated by CD44 knockdown[7].The T-ALL cell line LOUCY, which shows a transcriptional program related to immature T-ALL, exhibited high in vitro and in vivo sensitivity for ABT-199 in correspondence with high levels of BCL-2. In addition, ABT-199 showed synergistic therapeutic effects with different chemotherapeutic agents[3].When performed a genome-wide CRISPR knockout screen and found that inactivation of genes involved in mitochondrial translation restored sensitivity to ABT-199 in resistant AML cells. Pharmacologic inhibition of mitochondrial protein synthesis with antibiotics that target the ribosome, including tedizolid and doxycycline, effectively overcame ABT-199 resistance[6].
VU661013 is a novel, potent, selective MCL1 inhibitor. VU661013 was safely combined with ABT-199 for synergy in murine models of AML[3].ABT-199 and 5-Aza act synergistically to kill AML cells in vitro and display combinatorial antitumor activity in vivo[5]. Treatment with ABT-199 alone and in combination is well tolerated, with the most common side effects being neutropenia, infection, and gastrointestinal toxic effects[2].
参考文献:
[1]: Souers AJ, Leverson JD, et,al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb;19(2):202-8. doi: 10.1038/nm.3048. Epub 2013 Jan 6. PMID: 23291630.
[2]: Ramsey HE, Fischer MA, et,al. A Novel MCL1 Inhibitor Combined with ABT-199 Rescues ABT-199-Resistant Acute Myelogenous Leukemia. Cancer Discov. 2018 Dec;8(12):1566-1581. doi: 10.1158/2159-8290.CD-18-0140. Epub 2018 Sep 5. PMID: 30185627; PMCID: PMC6279595.
[3]: Bi C, Zhang X, et,al. Inhibition of 4EBP phosphorylation mediates the cytotoxic effect of mechanistic target of rapamycin kinase inhibitors in aggressive B-cell lymphomas. Haematologica. 2017 Apr;102(4):755-764. doi: 10.3324/haematol.2016.159160. Epub 2017 Jan 19. PMID: 28104700; PMCID: PMC5395116.
[4]: Gupta VA, Barwick BG, et,al. ABT-199 sensitivity in multiple myeloma is associated with B-cell gene expression. Blood. 2021 Jul 1;137(26):3604-3615. doi: 10.1182/blood.2020007899. PMID: 33649772; PMCID: PMC8462405.
[5]: Jin S, Cojocari D, et,al. 5-Azacitidine Induces NOXA to Prime AML Cells for ABT-199-Mediated Apoptosis. Clin Cancer Res. 2020 Jul 1;26(13):3371-3383. doi: 10.1158/1078-0432.CCR-19-1900. Epub 2020 Feb 13. PMID: 32054729.
[6]: Sharon D, Cathelin S, et,al. Inhibition of mitochondrial translation overcomes ABT-199 resistance in AML through activation of the integrated stress response. Sci Transl Med. 2019 Oct 30;11(516):eaax2863. doi: 10.1126/scitranslmed.aax2863. PMID: 31666400.
[7]: Yu X, Munoz-Sagredo L, et,al. CD44 loss of function sensitizes AML cells to the BCL-2 inhibitor ABT-199 by decreasing CXCL12-driven survival cues. Blood. 2021 Sep 23;138(12):1067-1080. doi: 10.1182/blood.2020006343. PMID: 34115113.
Venetoclax (ABT-199, GDC-0199) 是 Bcl-2 的选择性抑制剂，在无细胞试验中 K i 为 0.01 nM。与 Bcl-XL 和 Bcl-W 相比选择性高 4800 多倍，对 McL-1[1] 无抑制活性。
ABT-199 细胞杀伤具有选择性和机制因此，BCL2high 状态是对 ABT-199[1] 敏感性的潜在预测标志物。BIM 与 BCL2 的结合与 ABT-199 反应相关，并进一步表明敲除 BIM 会导致 ABT-199 降低灵敏度。 B 细胞基因的表达在 ABT-199 敏感性骨髓瘤中富集，尽管没有单个基因始终如一地描述敏感和耐药细胞[4]。在 ABT-199 抗性 OCI-AML3 细胞系中，CXCL12 促进表达高水平胚胎干细胞核心转录因子的细胞比例增加，CD44 敲低[7]。T-显示与未成熟 T-ALL 相关的转录程序的 ALL 细胞系 LOUCY 对 ABT-199 表现出高体外和体内敏感性，与高水平的 BCL-2 相对应。此外，ABT-199 显示出与不同化疗药物的协同治疗效果[3]。在进行全基因组 CRISPR 敲除筛选时，发现参与线粒体翻译的基因失活可恢复对 ABT-199 的敏感性在抗性 AML 细胞中。使用靶向核糖体的抗生素（包括泰地唑胺和多西环素）抑制线粒体蛋白质合成，有效克服了 ABT-199 耐药性[6]。
VU661013 是一种新型、有效、选择性MCL1抑制剂。 VU661013 与 ABT-199 安全结合，在小鼠 AML 模型中发挥协同作用[3]。ABT-199 和 5-Aza 在体外协同作用以杀死 AML 细胞，并在体内表现出联合抗肿瘤活性[5]。 ABT-199 单独和联合治疗的耐受性良好，最常见的副作用是中性粒细胞减少、感染和胃肠道毒性作用[2]。
| Kinase experiment [1]: | |
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Preparation Method |
The affinity of ABT-199 for different subtypes of the Bcl-2 family (Ki or IC50) was determined by competitive fluorescence polarization assays using the following peptide probe/protein pairs: F-BAD (1 nM) and Bcl-XL (6 nM),F-bax (1 nM) and Bcl-2 (10 nM), F-Bax (1 nM) and Bcl-W (40 nM), F-NOxa (2 nM) and McL-1 (40 nM),And the affinity of F-Bax (1 nM) and Bcl-2-A1(15 nM) for Bcl-XL was determined by time-resolved fluorescence resonance energy transfer assays.1 nM Tb labeled anti-His antibody,And ABT-199 were mixed for 30 min at room temperature on Envision microplate reader. Fluorescence values were measured using excitation filters at 340/35 nm and emission filters at 520/525 (F-BAK) and 495/510 nm (anti-His antibody labeled with Tb). |
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Reaction Conditions |
ABT-199 with Bcl-2 for 30 min at RT |
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Applications |
ABT-199 has a subnanomolar affinity for BCL-2 (Ki < 0.010 nM) and bound over three orders of magnitude less avidly to BCL-XL (Ki = 48 nM) and BCL-W (Ki = 245 nM) than to BCL-2. |
| Cell experiment [2]: | |
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Cell lines |
NHL cell lines |
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Preparation Method |
The viability of NHL cell lines was examined after 48 h incubation with increasing concentrations of Navitoclax or ABT-199. |
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Reaction Conditions |
0.01 μM -3.0 μM ABT-199 for 48h |
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Applications |
ABT-199 cell killing was selective and mechanism dependent, BCL2high status is thus a potential predictive marker for sensitivity to ABT-199. |
| Animal experiment [3]: | |
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Animal models |
Female C.B-17 SCID-beige mice |
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Preparation Method |
All xenograft trials were conducted using ten mice per group, and all mice were ear tagged and monitored individually throughout the studies. ABT-199 was formulated for oral dosing in 60% phosal 50 propylene glycol (PG), 30% polyethylene glycol (PEG) 400 and 10% ethanol. ABT-199 was delivered approximately 2 h before bendamustine or bendamustine plus rituximab. |
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Dosage form |
12.5 mg/kg ABT-199 for 60 days |
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Applications |
After a single oral dose of 12.5 mg per kg body weight in xenografts derived from RS4;11 cells (ALL), ABT-199 caused a maximal tumor growth inhibition (TGImax) of 47% and tumor growth delay (TGD) of 26%. |
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参考文献: [1].Souers AJ, Leverson JD,et,al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb;19(2):202-8. doi: 10.1038/nm.3048. Epub 2013 Jan 6. PMID: 23291630. |
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