2. Immunology/Inflammation
  3. PD-1/PD-L1
  4. PDL1 degrader-3

PDL1 degrader-3 (comppund e24) 是一种结合 CSN5 的抗肿瘤免疫调节剂，与人源 CSN5 的 Kd 为 4.53 μM。PDL1 degrader-3 可抑制 CSN5 的酶活性，提高 PD-L1 的泛素化水平，并通过泛素-蛋白酶体通路诱导 PD-L1 降解，降低肿瘤细胞膜上 PD-L1 的表达。PDL1 degrader-3 可阻断 PD-1/PD-L1 相互作用，激活肿瘤免疫微环境，增强肿瘤浸润性 T 细胞免疫功能，并抑制免疫抑制性 MDSCs 和 Tregs 的活化。PDL1 degrader-3 在小鼠肿瘤模型中发挥抗肿瘤作用。PDL1 degrader-3 可用于结直肠癌、肺癌的研究。

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PDL1 degrader-3

PDL1 degrader-3 Chemical Structure

CAS No. : 2488699-00-7

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PDL1 degrader-3 相关抗体

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  • 生物活性

  • 纯度 & 产品资料

  • 参考文献

生物活性

PDL1 degrader-3 (comppund e24) is a CSN5-binding antitumor immunomodulator with a human CSN5 Kd of 4.53 μM. PDL1 degrader-3 inhibits CSN5 enzymatic activity, increases PD-L1 ubiquitination, and induces PD-L1 degradation via the ubiquitin-proteasome pathway, reducing PD-L1 expression on tumor cell membranes. PDL1 degrader-3 blocks PD-1/PD-L1 interaction, activates the tumor immune microenvironment, enhances tumor-infiltrating T-cell immunity, and inhibits activation of immunosuppressive MDSCs and Tregs. PDL1 degrader-3 exerts antitumor effects in mouse tumor models. PDL1 degrader-3 can be used for the research of colorectal cancer, lung cancer[1].

体外研究
(In Vitro)

PDL1 degrader-3 (comppund e24) (20 μM; 24 h) 可强效降低人结直肠癌 RKO 细胞中的 PD-L1 蛋白表达，其活性优于 JQ-1，且细胞毒性较低[1]。
PDL1 degrader-3 (1-20 μM; 3-24 h) 可呈剂量和时间依赖性降低人结直肠癌 RKO 细胞及人肺癌 H1975 细胞中的 PD-L1 蛋白表达；24 h 后，在 RKO 细胞中浓度≥5 μM、H1975 细胞中浓度≥10 μM 时即可观察到显著下调，且两种细胞系在 20 μM 浓度下从 3 h 开始就出现显著下调[1]。
PDL1 degrader-3 (5-20 μM; 3-24 h) 可呈剂量和时间依赖性降低人结直肠癌 RKO 细胞及人肺癌 H1975 细胞的细胞膜 PD-L1 表达；在两种细胞系中，24 h 后 10 μM 和 20 μM 浓度下均观察到显著下调，且从 6 h 开始 20 μM 浓度下即出现显著下调[1]。
PDL1 degrader-3 (5-20 μM; 24 h) 可通过免疫荧光检测显示，以剂量依赖方式降低人结直肠癌 RKO 细胞和人肺癌 H1975 细胞中的 PD-L1 蛋白表达，在 24 h 后 10 μM 和 20 μM 浓度下表现出显著下调作用[1]。
PDL1 degrader-3 (5-20 μM; 24 h) 在浓度高达 20 μM、作用 24 h 的条件下，不会显著降低人结直肠癌 RKO 细胞或人肺癌 H1975 细胞的细胞活力[1]。
PDL1 degrader-3 (20 μM; 24 h) 可显著抑制人结直肠癌 RKO 细胞和人肺癌 H1975 细胞中 PD-L1/PD-1 的结合[1]。
PDL1 degrader-3 (5-20 μM; 24 h) 可呈剂量依赖性增强 T 细胞介导的对人结直肠癌 RKO 细胞和人肺癌 H1975 细胞的杀伤作用[1]。
PDL1 degrader-3 (1-20 μM; 3-24 h) 对人结直肠癌 RKO 细胞中 PD-L1 mRNA 的表达无显著影响 (最高浓度 20 μM、最长作用时间 24 h)，表明 PD-L1 的下调发生在蛋白水平[1]。
PDL1 degrader-3 (20 μM; up to 12 h) 在与 60 μg/mL CHX 共同处理长达 12 h 时，可显著缩短人结直肠癌 RKO 细胞中 PD-L1 蛋白的半衰期[1]。
PDL1 degrader-3 (20 μM; 12 h) 可通过泛素-蛋白酶体通路诱导人结直肠癌 RKO 细胞和人肺癌 H1975 细胞中的 PD-L1 降解，因为 10 μM MG132 可阻断该效应，而溶酶体或自噬抑制剂则无此作用[1]。
PDL1 degrader-3 (20 μM; 6 h) 可显著提高人结直肠癌 RKO 细胞中 PD-L1 的多泛素化水平，证实其通过泛素-蛋白酶体途径实现降解[1]。
PDL1 degrader-3 (20 μM; 24 h post-transfection) 在人结直肠癌 RKO 细胞中诱导的 PD-L1 下调依赖于 CSN5，因为过表达 CSN5 可阻断该作用，而敲低则会增强该作用[1]。
PDL1 degrader-3 (10-320 μM; 3 min) 可直接结合人结直肠癌 RKO 细胞中的 CSN5 蛋白，表现为 CSN5 的热稳定性呈浓度依赖性升高[1]。
PDL1 degrader-3 可特异性结合野生型 CSN5，其 Kd 为 4.53 μM，关键结合相互作用由 Asp151 和 Lys210 残基介导[1]。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

PDL1 degrader-3 相关抗体:

Western Blot Analysis[1]

Cell Line: human colorectal cancer RKO cells
Concentration: 20 μM
Incubation Time: 24 h
Result: Reduced PD-L1 protein expression more effectively than the positive control JQ-1.
Showed minimal cytotoxicity at 20 μM.

Western Blot Analysis[1]

Cell Line: human colorectal cancer RKO cells, human lung cancer H1975 cells
Concentration: 1-20 μM (24 h treatment); 20 μM (time-course treatment)
Incubation Time: 24 h (concentration-gradient treatment); 3-24 h (20 μM treatment)
Result: Caused concentration-dependent reduction in PD-L1 protein levels in RKO cells, with significant decreases at 5, 10, 15, 20 μM after 24 h.
Caused time-dependent reduction in RKO cells, with significant decreases starting at 3 h with 20 μM.
Caused concentration-dependent reduction in H1975 cells, with significant decreases at 10, 15, 20 μM after 24 h.
Caused time-dependent reduction in H1975 cells, with significant decreases starting at 3 h with 20 μM.

Immunofluorescence[1]

Cell Line: human colorectal cancer RKO cells, human lung cancer H1975 cells
Concentration: 5-20 μM
Incubation Time: 24 h
Result: Caused concentration-dependent reduction in PD-L1 fluorescence intensity in both RKO and H1975 cells, with significant decreases at 10 and 20 μM.

Cell Proliferation Assay[1]

Cell Line: human colorectal cancer RKO cells, human lung cancer H1975 cells
Concentration: 5-20 μM
Incubation Time: 24 h
Result: Did not significantly reduce cell viability in either RKO or H1975 cells, with no significant differences compared to the control group.

Immunofluorescence[1]

Cell Line: human colorectal cancer RKO cells, human lung cancer H1975 cells
Concentration: 20 μM
Incubation Time: 24 h
Result: Significantly reduced green fluorescence intensity in both RKO and H1975 cells, indicating a significant decrease in PD-L1/PD-1 binding.

Cell Cytotoxicity Assay[1]

Cell Line: human colorectal cancer RKO cells, human lung cancer H1975 cells
Concentration: 5-20 μM
Incubation Time: 24 h
Result: Significantly enhanced T cell-mediated killing of RKO and H1975 cells, with a concentration-dependent reduction in surviving tumor cells.

RT-PCR[1]

Cell Line: human colorectal cancer RKO cells
Concentration: 1-20 μM (24 h treatment); 20 μM (time-course treatment)
Incubation Time: 24 h (concentration-gradient treatment); 3-24 h (20 μM treatment)
Result: Did not significantly alter PD-L1 mRNA levels compared to the control in RKO cells after 24 h at 1-20 μM.
Did not significantly alter PD-L1 mRNA levels compared to the control in RKO cells at 20 μM for 3-24 h.

Western Blot Analysis[1]

Cell Line: human colorectal cancer RKO cells
Concentration: 20 μM (co-treated with 60 μg/mL CHX)
Incubation Time: 0-12 h
Result: Significantly reduced the half-life of PD-L1 protein in RKO cells compared to treatment with CHX alone.

Western Blot Analysis[1]

Cell Line: human colorectal cancer RKO cells, human lung cancer H1975 cells
Concentration: 20 μM (co-treated with 1-10 μM MG132; 20-40 μM CQ; 20-40 μM 3-MA)
Incubation Time: 12 h
Result: Co-treatment with 20 μM and 10 μM MG132 completely blocked the PDL1 degrader-3-induced reduction in PD-L1 protein levels in both RKO and H1975 cells.
Co-treatment with 20 μM and 20, 40 μM CQ or 20, 40 μM 3-MA did not block PD-L1 reduction in both RKO and H1975 cells.

Western Blot Analysis[1]

Cell Line: human colorectal cancer RKO cells
Concentration: 20 μM (co-treated with MG132)
Incubation Time: 6 h
Result: Significantly increased the polyubiquitination level of PD-L1 protein in RKO cells.

Western Blot Analysis[1]

Cell Line: human colorectal cancer RKO cells
Concentration: 20 μM
Incubation Time: 24 h (post-transfection with CSN5 overexpression plasmid or siRNA for 24 h)
Result: Overexpression of CSN5 completely reversed the PDL1 degrader-3-induced reduction in PD-L1 protein levels.
Knockdown of CSN5 enhanced the PDL1 degrader-3-induced reduction in PD-L1 protein levels.
体内研究
(In Vivo)

PDL1 degrader-3 (comppund e24) (腹腔注射；每日给药；连续 16 天，剂量 2.5-10 mg/kg) 可抑制 C57BL/6J 小鼠皮下 MC38 结直肠癌的生长，在 10 mg/kg 剂量下肿瘤生长抑制率最高可达 78.88%，同时可剂量依赖性地减少免疫抑制性 Treg 和 MDSC，并激活肿瘤浸润 CD8+ T 细胞[1]。
PDL1 degrader-3 (腹腔注射，每日 1 次，连续 16 天，剂量 2.5-5 mg/kg) 可抑制 C57BL/6J 小鼠皮下 Lewis 肺癌的生长，在 5 mg/kg 剂量下的肿瘤生长抑制率达 88.56%，同时可调控肿瘤免疫微环境以增强抗肿瘤免疫活性[1]。
PDL1 degrader-3 (腹腔注射，10 mg/kg，每日 1 次，连续 16 天) 不会抑制 T 细胞缺陷裸鼠的皮下 MC38 结直肠癌生长，证实其抗肿瘤活性依赖功能性 T 细胞[1]。
PDL1 degrader-3 (5 mg/kg，腹腔注射，每日 1 次，共 16 天) 不会抑制 T 细胞缺陷裸鼠的皮下 Lewis 肺癌生长，证实其抗肿瘤活性需要功能性 T 细胞[1]。
PDL1 degrader-3 (10 mg/kg；腹腔注射；每日一次；连续 18 天) 与抗 CTLA-4 抗体联用，在 C57BL/6J 小鼠中增强抗肿瘤免疫并抑制皮下 MC38 结直肠癌生长的效果优于任一单药疗法[1]。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: C57BL/6J (female, 6 weeks old, subcutaneous injection of 8 × 105 MC38 mouse colorectal cancer cells)[1]
Dosage: 2.5 mg/kg; 5 mg/kg; 10 mg/kg
Administration: i.p.; daily; 16 days
Result: Achieved a 38.79% tumor growth inhibition rate at 2.5 mg/kg.
Achieved a 53.09% tumor growth inhibition rate at 5 mg/kg.
Achieved a 78.88% tumor growth inhibition rate at 10 mg/kg.
Reduced the frequency of tumor-infiltrating FOXP3+CD25+ Tregs from 34.2% in controls to 25.2%, 17.0%, and 6.81% at 2.5, 5, and 10 mg/kg respectively.
Reduced the frequency of CD11b+Gr-1+ MDSCs from 30.1% in controls to 23.9%, 14.9%, and 10.2% at 2.5, 5, and 10 mg/kg respectively.
Increased the frequency of GzmB+ CD8+ T cells from 4.53% in controls to 10.7%, 15.5%, and 26.3% at 2.5, 5, and 10 mg/kg respectively.
Animal Model: C57BL/6J (female, 6 weeks old, subcutaneous injection of 8 × 105 Lewis mouse lung cancer cells)[1]
Dosage: 2.5 mg/kg; 5 mg/kg
Administration: i.p.; daily; 16 days
Result: Achieved a 9.16% tumor growth inhibition rate at 2.5 mg/kg.
Achieved an 88.56% tumor growth inhibition rate at 5 mg/kg.
Reduced tumor-infiltrating immunosuppressive cells.
Increased activated CD8+ T cell frequency in tumor tissue.
Animal Model: C57BL/6J (female, 6 weeks old, subcutaneous injection of 8 × 105 MC38 mouse colorectal cancer cells)[1]
Dosage: 10 mg/kg (in combination with anti-CTLA-4 antibody 100 μg per mouse)
Administration: i.p.; daily (e24), every 5 days (anti-CTLA-4); 18 days
Result: Resulted in greater tumor growth inhibition than either monotherapy.
Reduced tumor weight significantly compared to controls.
Reduced tumor-infiltrating FOXP3+CD25+ Tregs to 4.24%.
Reduced CD11b+Gr-1+ MDSCs to 9.03%.
Increased GzmB+ CD8+ T cells to 35.3%.
Reduced FOXP3 expression and increased CD3 expression in tumor tissue compared to controls and monotherapy groups.
分子量

264.28

Formula

C16H12N2O2
CAS 号
运输条件

Room temperature in continental US; may vary elsewhere.
储存方式

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参考文献

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Keywords:

PDL1 degrader-32488699-00-7PD-1/PD-L1PD-1/Programmed death-ligand 1PD-1tumor-infiltrating T-cellRKO cellsTregsubiquitin-proteasome pathwayCSN5tumor immune microenvironmentcolorectal cancerMDSCsPD-L1Inhibitorinhibitorinhibit

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