DT2216
目录号 : GC39708
DT2216 是一种蛋白水解靶向嵌合体 (PROTAC)，靶向 Bcl-xL 降解依赖于 Bcl-2 家族过表达蛋白（如 Bcl-2、Bcl-xL 和 Mcl-1）的 T 细胞淋巴瘤。
Cas No.:2365172-42-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
MyLa cells |
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Preparation Method |
MyLa cells were pretreated with or without QVD for 4 h, and then treated with DT2216 for different duration. |
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Reaction Conditions |
0, 0.01, 0.03, 0.1, 0.3µM for 16h |
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Applications |
DT2216 dose- and time-dependently decreased the expression of Bcl-xL but had no effect on the expression of BCL2L1 (the gene that encodes Bcl-xL) mRNA in MyLa cells |
| Animal experiment [2]: | |
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Animal models |
Pancreatic cancer PDX models were established by NSG mice |
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Preparation Method |
Animals were treated with vehicle, gemcitabine [20 mg/kg, once a week (every 7 days), i.p.], DT2216 [15 mg/kg, every 4 days, i.p.] and a combination of gemcitabine and DT2216. DT2216 was formulated in 50% phosal 50 PG, 45% miglyol 810N and 5% polysorbate 80. |
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Dosage form |
Intraperitoneal injection, 15 mg/kg, every 4 days |
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Applications |
DT2216 inhibited tumor growth and increasing the survival of the tumor-bearing mice, whereas the combination treatment was more effective than either agent alone without any significant decrease in body weight. |
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References: [1]: He Y, Koch R, Budamagunta V, et al. DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas[J]. Journal of hematology & oncology, 2020, 13(1): 1-13. | |
DT2216 is a proteolysis targeting chimera (PROTAC), and targets Bcl-xL for degradation in T-cell lymphomas that depend on the overexpressed proteins of the Bcl-2 family, such as Bcl-2, Bcl-xL, and Mcl-1[1,2].
DT2216 inhibited G-68 cells with IC50 value of 4.02 μM (72hours). Combination of 0.1μM DT2216 and 0.1μM gemcitabine treatment synergistically kills pancreatic cancer cells in vitro [3].
DT2216 showed remarkable effects in xenograft mouse model of human T-cell lymphoma (MyLa, MJ, MAC2A, and L82 cell lines) and T-cell prolymphocytic leukemia (T-PLL), with reduced platelet toxicity compared with ABT263 [1]. DT2216 effect was also present in a patient-derived xenograft tumor model of resistant T-cell ALL, when DT2216 was combined with vincristine, dexamethasone, and L-asparaginase. The median overall survival of mice reached 72 days with combination treatment versus 55 days with DT2216 monotherapy, and 47 days with chemotherapy alone [4].
References:
[1]. He Y, Koch R, Budamagunta V, et al. DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas[J]. Journal of hematology & oncology, 2020, 13(1): 1-13.
[2]. Khan, S.; Zhang, X.; Lv, D.; Zhang, Q.; He, Y.; Zhang, P.; Liu, X.; Thummuri, D.; Yuan, Y.; Wiegand, J.S.; et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019, 25, 1938-1947.
[3]. Thummuri D, Khan S, Underwood P W, et al. Overcoming Gemcitabine Resistance in Pancreatic Cancer Using the BCL-XL-Specific Degrader DT2216[J]. Molecular cancer therapeutics, 2022, 21(1): 184-192.
[4]. Wolska-Washer A, Smolewski P. Targeting protein degradation pathways in tumors: Focusing on their role in hematological malignancies[J]. Cancers, 2022, 14(15): 3778.
DT2216 是一种蛋白水解靶向嵌合体 (PROTAC)，靶向 Bcl-xL 降解依赖于 Bcl-2 家族过表达蛋白（例如 Bcl-2、Bcl-xL 和 Mcl）的 T 细胞淋巴瘤-1[1,2].
DT2216 抑制 G-68 细胞，IC50 值为 4.02 μM（72 小时）。 0.1μM DT2216 和 0.1μM 吉西他滨联合治疗可在体外协同杀死胰腺癌细胞[3]。
DT2216 在人 T 细胞淋巴瘤（MyLa、MJ、MAC2A 和 L82 细胞系）和 T 细胞幼淋巴细胞白血病 (T-PLL) 的异种移植小鼠模型中显示出显着效果，与 ABT263 相比血小板毒性降低 [1]。当 DT2216 与长春新碱、地塞米松和 L-天冬酰胺酶联合使用时，DT2216 效应也存在于耐药 T 细胞 ALL 患者来源的异种移植肿瘤模型中。联合治疗组小鼠的中位总生存期达到 72 天，而 DT2216 单药治疗组为 55 天，单独化疗组为 47 天[4]。
| Cas No. | 2365172-42-3 | SDF | |
| Canonical SMILES | CC1(C)CCC(C2=CC=C(Cl)C=C2)=C(C1)CN3CCN(C4=CC=C(C(NS(=O)(C5=CC(S(C(F)(F)F)(=O)=O)=C(N[C@@H](CSC6=CC=CC=C6)CCN7CCN(C(CCCCCC(N[C@@H](C(C)(C)C)C(N8[C@@H](C[C@@H](O)C8)C(N[C@H](C9=CC=C(C%10=C(N=CS%10)C)C=C9)C)=O)=O)=O)=O)CC7)C=C5)=O)=O)C=C4)CC3 | ||
| 分子式 | C77H96ClF3N10O10S4 | 分子量 | 1542.36 |
| 溶解度 | DMSO: 25 mg/mL (16.21 mM) | 储存条件 | Store at -20°C,stored under nitrogen |
| 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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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.6484 mL | 3.2418 mL | 6.4836 mL |
| 5 mM | 0.1297 mL | 0.6484 mL | 1.2967 mL |
| 10 mM | 0.0648 mL | 0.3242 mL | 0.6484 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers
J Hematol Oncol 2022 Mar 9;15(1):23.PMID:35260176DOI:10.1186/s13045-022-01241-3.
KRAS mutations are the most common oncogenic drivers. Sotorasib (AMG510), a covalent inhibitor of KRASG12C, was recently approved for the treatment of KRASG12C-mutated non-small cell lung cancer (NSCLC). However, the efficacy of sotorasib and other KRASG12C inhibitors is limited by intrinsic resistance in colorectal cancer (CRC) and by the rapid emergence of acquired resistance in all treated tumors. Therefore, there is an urgent need to develop novel combination therapies to overcome sotorasib resistance and to maximize its efficacy. We assessed the effect of sotorasib alone or in combination with DT2216 (a clinical-stage BCL-XL proteolysis targeting chimera [PROTAC]) on KRASG12C-mutated NSCLC, CRC and pancreatic cancer (PC) cell lines using MTS cell viability, colony formation and Annexin-V/PI apoptosis assays. Furthermore, the therapeutic efficacy of sotorasib alone and in combination with DT2216 was evaluated in vivo using different tumor xenograft models. We observed heterogeneous responses to sotorasib alone, whereas its combination with DT2216 strongly inhibited viability of KRASG12C tumor cell lines that partially responded to sotorasib treatment. Mechanistically, sotorasib treatment led to stabilization of BIM and co-treatment with DT2216 inhibited sotorasib-induced BCL-XL/BIM interaction leading to enhanced apoptosis in KRASG12C tumor cell lines. Furthermore, DT2216 co-treatment significantly improved the antitumor efficacy of sotorasib in vivo. Collectively, our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore, its combination with a pro-apoptotic agent, i.e., DT2216, shows synergistic responses and can potentially overcome resistance.
Overcoming Gemcitabine Resistance in Pancreatic Cancer Using the BCL-XL-Specific Degrader DT2216
Mol Cancer Ther 2022 Jan;21(1):184-192.PMID:34667112DOI:10.1158/1535-7163.MCT-21-0474.
Pancreatic cancer is the third most common cause of cancer-related deaths in the United States. Although gemcitabine is the standard of care for most patients with pancreatic cancer, its efficacy is limited by the development of resistance. This resistance may be attributable to the evasion of apoptosis caused by the overexpression of BCL-2 family antiapoptotic proteins. In this study, we investigated the role of BCL-XL in gemcitabine resistance to identify a combination therapy to more effectively treat pancreatic cancer. We used CRISPR-Cas9 screening to identify the key genes involved in gemcitabine resistance in pancreatic cancer. Pancreatic cancer cell dependencies on different BCL-2 family proteins and the efficacy of the combination of gemcitabine and DT2216 (a BCL-XL proteolysis targeting chimera or PROTAC) were determined by MTS, Annexin-V/PI, colony formation, and 3D tumor spheroid assays. The therapeutic efficacy of the combination was investigated in several patient-derived xenograft (PDX) mouse models of pancreatic cancer. We identified BCL-XL as a key mediator of gemcitabine resistance. The combination of gemcitabine and DT2216 synergistically induced cell death in multiple pancreatic cancer cell lines in vitro In vivo, the combination significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice compared with the individual agents in pancreatic cancer PDX models. Their synergistic antitumor activity is attributable to DT2216-induced degradation of BCL-XL and concomitant suppression of MCL-1 by gemcitabine. Our results suggest that DT2216-mediated BCL-XL degradation augments the antitumor activity of gemcitabine and their combination could be more effective for pancreatic cancer treatment.
A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity
Nat Med 2019 Dec;25(12):1938-1947.PMID:31792461DOI:10.1038/s41591-019-0668-z.
B-cell lymphoma extra large (BCL-XL) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-XL proteolysis-targeting chimera (PROTAC), that targets BCL-XL to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-XL-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-XL.
DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas
J Hematol Oncol 2020 Jul 16;13(1):95.PMID:32677976DOI:10.1186/s13045-020-00928-9.
Background: Patients with advanced T cell lymphomas (TCLs) have limited therapeutic options and poor outcomes in part because their TCLs evade apoptosis through upregulation of anti-apoptotic Bcl-2 proteins. Subsets of TCL cell lines, patient-derived xenografts (PDXs), and primary patient samples depend on Bcl-xL for survival. However, small molecule Bcl-xL inhibitors such as ABT263 have failed during clinical development due to on-target and dose-limiting thrombocytopenia. Methods: We have developed DT2216, a proteolysis targeting chimera (PROTAC) targeting Bcl-xL for degradation via Von Hippel-Lindau (VHL) E3 ligase, and shown that it has better anti-tumor activity but is less toxic to platelets compared to ABT263. Here, we examined the therapeutic potential of DT2216 for TCLs via testing its anti-TCL activity in vitro using MTS assay, immunoblotting, and flow cytometry and anti-TCL activity in vivo using TCL cell xenograft and PDX model in mice. Results: The results showed that DT2216 selectively killed various Bcl-xL-dependent TCL cells including MyLa cells in vitro. In vivo, DT2216 alone was highly effective against MyLa TCL xenografts in mice without causing significant thrombocytopenia or other toxicity. Furthermore, DT2216 combined with ABT199 (a selective Bcl-2 inhibitor) synergistically reduced disease burden and improved survival in a TCL PDX mouse model dependent on both Bcl-2 and Bcl-xL. Conclusions: These findings support the clinical testing of DT2216 in patients with Bcl-xL-dependent TCLs, both as a single agent and in rational combinations.
Strategies to Reduce the On-Target Platelet Toxicity of Bcl-xL Inhibitors: PROTACs, SNIPERs and Prodrug-Based Approaches
Chembiochem 2022 Jun 20;23(12):e202100689.PMID:35263486DOI:10.1002/cbic.202100689.
Apoptosis is a highly regulated cellular process. Aberration in apoptosis is a common characteristic of various disorders. Therefore, proteins involved in apoptosis are prime targets in multiple therapies. Bcl-xL is an antiapoptotic protein. Compared to other antiapoptotic proteins, the expression of Bcl-xL is common in solid tumors and, to an extent, in some leukemias and lymphomas. The overexpression of Bcl-xL is also linked to survival and chemoresistance in cancer and senescent cells. Therefore, Bcl-xL is a promising anticancer and senolytic target. Various nanomolar range Bcl-xL inhibitors have been developed. ABT-263 was successfully identified as a Bcl-xL /Bcl-2 dual inhibitor. But it failed in the clinical trial (phase-II) because of its on-target platelet toxicity, which also implies an essential role of Bcl-xL protein in the survival of human platelets. Classical Bcl-xL inhibitor designs utilize occupancy-driven pharmacology with typical shortcomings (such as dose-dependent off-target and on-target platelet toxicities). Hence, event-driven pharmacology-based approaches, such as proteolysis targeting chimeras (PROTACs) and SNIPERs (specific non-genetic IAP-based protein erasers) have been developed. The development of Bcl-xL based PROTACs was expected, as 600 E3-ligases are available in humans, while some (such as cereblon (CRBN), von Hippel-Lindau (VHL)) are relatively less expressed in platelets. Therefore, E3 ligase ligand-based Bcl-xL PROTACs (CRBN: XZ424, XZ739; VHL: DT2216, PZ703b, 753b) showed a significant improvement in platelet therapeutic index than their parent molecules (ABT-263: DT2216, PZ703b, 753b, XZ739, PZ15227; A1155463: XZ424). Other than their distinctive pharmacology, PROTACs are molecularly large, which limits their cell permeability and plays a role in improving their cell selectivity. We also discuss prodrug-based approaches, such as antibody-drug conjugates (ABBV-155), phosphate prodrugs (APG-1252), dendrimer conjugate (AZD0466), and glycosylated conjugates (Nav-Gal). Studies of in-vitro, in-vivo, structure-activity relationships, biophysical characterization, and status of preclinical/clinical inhibitors derived from these strategies are also discussed in the review.