PNU-159682, a metabolite of the anthracycline Nemorubicin, is a highly potent DNA topoisomerase II inhibitor with excellent cytotoxicity^[1]. PNU-159682 acts as a more potent and tolerated ADC cytotoxin than Doxorubicin for ADC synthesis^[2]. PNU-159682 can be used in EDV-nanocell technology to overcome drug resistance^[3].

PNU-159682 (0-500 nM; exposed to the compounds for 1 hour and then cultured in compound-free medium for 72 hours) has cytotoxic effects on human tumor cell lines in a sulforhodamine B assay. The IC₇₀ values are 0.577 nM, 0.39 nM, 0.128 nM, and 0.081 nM, 0.086 nM and 0.075 nM for HT-29, A2780, DU145, EM-2, Jurkat and CEM cells, respectively^[1]. It against human tumor cell lines with IC₇₀ in the ranging 68 nM-578 nM and 181 nM-1717 nM towards MMDX and doxorubicin, respectively^[1].
PNU-159682 is more potent than MMAE on NHL cell lines. In a cell viability assay, PNU-159682 is against BJAB.Luc, Granta-519, SuDHL4.Luc, and WSU-DLCL2 with IC₅₀ values of 0.10 nM, 0.020 nM, 0.055 nM, and 0.1 nM, respectively. While MMAE is against BJAB.Luc, Granta-519, SuDHL4.Luc, and WSU-DLCL2 with IC₅₀ values of 0.54 nM, 0.25 nM, 1.19 nM and 0.25 nM, respectively^[2].
PNU-159682 is thousands of times more cytotoxic than doxorubicin and can be used to develop a new class of ADCs. PNU159682 to anti-CD22 antibody (anti-CD22-NMS249) exhibits strong anti-tumor effects in vitro. Anti-CD22-NMS249 (PNU159682 to anti-CD22 antibody) is active in in vitro viability assays of NHL cell lines and is 2 to 20 fold more potent than pinatuzumab vedotin, the ADC anti-CD22-NMS249 is against BJAB.Luc, Granta-519, SuDHL4.Luc, and WSU-DLCL2 with IC₅₀ values of 0.058 nM, 0.030 nM, 0.0221 nM, and 0.01 nM, respectively^[3].
PNU-159682 (100 μM) weakly inhibits topoisomerase II unknotting activity. PNU-159682 shows cytotoxic effect on CAIX-expressing SKRC-52 cells with IC₅₀ of 25 nM^[4].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

PNU-159682 (single-dose; i.v.15 μg/kg) is a maximum tolerated dose in murine L1210 leukemia model. PNU-159682 shows an improved antitumor activity in vivo. The antitumor effect of PNU-159682 (increase in life span=29%) is comparable to that afforded by 90 μg/kg MMDX (increase in life=36%)^[1].
PNU-159682 (i.v. 4 μg/kg; q7dx3; 40 days) has a therapeutic response in MX-1 human mammary carcinoma mice. What’s more, from day 39, four out of seven mice receiving PNU-159682 exhibits complete tumor regression^[1].
PNU-159682 is more cytotoxic than doxorubicin and can be used to develop a new class of ADCs. PNU159682 to anti-CD22 antibody (anti-CD22-NMS249) exhibits strong anti-tumor effects in vivo. ADC dose (anti-CD22-NMS249; 50 µg/m2 conjugated PNU-159682) is well tolerated in mice and results in less than 10% weight loss^[2].
In the BJAB.Luc model the efficacy of antiCD22-NMS249 (single dose; 2 mg/kg) is similar to anti-CD22-vc-MMAE. At 2 mg/kg dosage, antiCD22-NMS249 gives complete remission of the tumors (NMS249: 110-134%TGI vs. vc-MMAE: 114-143%TGI). Additionally, a single dose of antiCD22-NMS249 at 2 mg/kg results in tumor stasis for three weeks^[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

641.62

C₃₂H₃₅NO₁₃

202350-68-3

Room temperature in continental US; may vary elsewhere.

4°C, stored under nitrogen

*In solvent : -80°C, 6 months; -20°C, 1 month (stored under nitrogen)

In Vitro: 

DMSO : 100 mg/mL (155.86 mM; Need ultrasonic)

*

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, 6 months; -20°C, 1 month (stored under nitrogen)。-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。

In Vivo:

请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液，再依次添加助溶剂：

——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用； 以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

• 1.

  请依序添加每种溶剂： 10% DMSO    40% PEG300    5% Tween-80    45% saline

  Solubility: ≥ 2.5 mg/mL (3.90 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (3.90 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。

  将 0.9 g 氯化钠，完全溶解于 100 mL ddH₂O 中，得到澄清透明的生理盐水溶液

• 2.

  请依序添加每种溶剂： 10% DMSO    90% (20% SBE-β-CD in saline)

  Solubility: 2.5 mg/mL (3.90 mM); Suspended solution; Need ultrasonic

  此方案可获得 2.5 mg/mL (3.90 mM) 的均匀悬浊液，悬浊液可用于口服和腹腔注射。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。

  将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中，再用生理盐水定容至 10 mL，完全溶解，澄清透明
• 3.

  请依序添加每种溶剂： 10% DMSO    90% corn oil

  Solubility: ≥ 2.5 mg/mL (3.90 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (3.90 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。

• [1]. Quintieri L, et al. Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes. Clin Cancer Res. 2005 Feb 15;11(4):1608-17.

  [2]. Cazzamalli S, et al. Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma. Mol Cancer Ther. 2016 Dec;15(12):2926-2935.

  [3]. Pengxuan Zhao, et al. Recent advances of antibody drug conjugates for clinical applications. Acta Pharm Sin B. 2020 Sep;10(9):1589-1600.

  [4]. Joanne Lundy, Interim data: Phase I/IIa study of EGFR-targeted EDV nanocells carrying cytotoxic drug PNU-159682 (E-EDV-D682) with immunomodulatory adjuvant EDVs carrying α-galactosyl ceramide (EDV-GC) in patients with recurrent, metastatic pancreatic cancer. GASTROINTESTINAL CANCER—GASTROESOPHAGEAL, PANCREATIC, AND HEPATOBILIARY