ABT-199
(Synonyms: 维奈妥拉; ABT-199; GDC-0199; Venetoclax) 目录号 : GC14069
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。
Cas No.:1257044-40-8
Sample solution is provided at 25 µL, 10mM.
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- Datasheet
| 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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References: [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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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].
References:
[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]。
| Cas No. | 1257044-40-8 | SDF | |
| 别名 | 维奈妥拉; ABT-199; GDC-0199; Venetoclax | ||
| 化学名 | 4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide | ||
| Canonical SMILES | CC1(CCC(=C(C1)C2=CC=C(C=C2)Cl)CN3CCN(CC3)C4=CC(=C(C=C4)C(=O)NS(=O)(=O)C5=CC(=C(C=C5)NCC6CCOCC6)[N+](=O)[O-])OC7=CN=C8C(=C7)C=CN8)C | ||
| 分子式 | C45H50ClN7O7S | 分子量 | 868.44 |
| 溶解度 | ≥ 43.422mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.1515 mL | 5.7575 mL | 11.5149 mL |
| 5 mM | 0.2303 mL | 1.1515 mL | 2.303 mL |
| 10 mM | 0.1151 mL | 0.5757 mL | 1.1515 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.
Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia
B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profiling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML.
ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development
With the advent of new agents targeting CD20, Bruton's tyrosine kinase, and phosphoinositol-3 kinase for chronic lymphoid leukemia (CLL), more treatment options exist than ever before. B-cell lymphoma-2 (BCL-2) plays a major role in cellular apoptosis and is a druggable target. Small molecule inhibitors of BCL-2 are in active clinical studies. ABT-199 (venetoclax, RG7601, GDC-0199) has been granted breakthrough designation by FDA for relapsed or refractory CLL with 17p deletion. In this review, we summarized the latest clinical development of ABT-199/venetoclax and other novel agents targeting the BCL-2 proteins.
Venetoclax-based therapies for acute myeloid leukemia
The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.
Apatinib enhances chemosensitivity of ABT-199 in diffuse large B-cell lymphoma
To investigate the effect of Apatinib (an inhibitor targeting VEGFR-2) enhances chemosensitivity of ABT-199 on diffuse large B-cell lymphoma (DLBCL). Viability assay and flow cytometric assay for determining apoptosis, cell cycle, mitochondrial membrane potential, reactive oxygen species and immunoblotting were used to explore the combination effect in DLBCL cell lines, DLBCL patient samples, and DLBCL mouse models. RNA sequencing assay helped identify mechanisms of ABT-199 plus Apatinib. The results show that ABT-199 combined with Apatinib inhibited cell proliferation, reduced colony-forming capacity, and induced apoptosis and cell cycle arrest in DLBCL cells. Mechanistically, the combination therapy inhibited tumour cell growth and promoted tumour cell death by regulating EDN1 and MAPK-related pathways and activating the intrinsic apoptotic pathway. The effect of the combination therapy was also validated in primary DLBCL blasts and xenograft mouse models. Our findings indicate that Apatinib enhances the chemosensitivity of ABT-199 and might serve as a promising therapeutic strategy for DLBCL.