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Pyrrolobenzodiazepine Dimer Antibody–Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-11-16 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00736 Stephen J. Gregson 1 , Luke A. Masterson 1 , Binqing Wei 2 , Thomas H. Pillow 2 , Susan D. Spencer 2 , Gyoung-Dong Kang 1 , Shang-Fan Yu 2 , Helga Raab 2 , Jeffrey Lau 2 , Guangmin Li 2 , Gail D. Lewis Phillips 2 , Janet Gunzner-Toste 2 , Brian S. Safina 2 , Rachana Ohri 2 , Martine Darwish 2 , Katherine R. Kozak 2 , Josefa dela Cruz-Chuh 2 , Andrew Polson 2 , John A. Flygare 2 , Philip W. Howard 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-11-16 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00736 Stephen J. Gregson 1 , Luke A. Masterson 1 , Binqing Wei 2 , Thomas H. Pillow 2 , Susan D. Spencer 2 , Gyoung-Dong Kang 1 , Shang-Fan Yu 2 , Helga Raab 2 , Jeffrey Lau 2 , Guangmin Li 2 , Gail D. Lewis Phillips 2 , Janet Gunzner-Toste 2 , Brian S. Safina 2 , Rachana Ohri 2 , Martine Darwish 2 , Katherine R. Kozak 2 , Josefa dela Cruz-Chuh 2 , Andrew Polson 2 , John A. Flygare 2 , Philip W. Howard 1
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Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody–drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7), or piperazine (8) link to the PBD. In vitro IC50 values were 11–48 ng/mL in HER2 3+ SK-BR-3 and KPL-4 (7 inactive) for the anti-HER2 ADCs (HER2 0 MCF7, all inactive) and 0.10–1.73 μg/mL (7 inactive) in CD22 3+ BJAB and WSU-DLCL2 for anti-CD22 ADCs (CD22 0 Jurkat, all inactive at low doses). In vivo antitumor efficacy for the anti-HER2 ADCs in Founder 5 was observed with tumor stasis at 0.5–1 mg/kg, 1 mg/kg, and 3–6 mg/kg for 6, 8, and 7, respectively. Tumor stasis at 2 mg/kg was observed for anti-CD22 6 in WSU-DLCL2. In summary, noncleavable PBD-ADCs exhibit potent activity, particularly in HER2 models.
中文翻译：
吡咯并苯二氮杂二聚体抗体-药物缀合物：不可裂解的药物接头的合成和评价。
通过中间体19合成了三个经过合理设计的吡咯并苯并二氮杂卓（PBD）药物接头，用于抗体-药物偶联物（ADC）。它们在接头中缺乏可裂解的触发物，由用于半胱氨酸抗体偶联的顺丁烯二酰亚胺，亲水性间隔基以及与PBD的炔烃（6），三唑（7）或哌嗪（8）相连。抗HER2 ADC的HER2 3+ SK-BR-3和KPL-4（7个未激活）的体外IC 50值为11–48 ng / mL ，0.12–1.73μg/ mL是HER2 0+ MCF7，全部不激活（7抗CD22 ADC的CD22 3+ BJAB和WSU-DLCL2中处于非活动状态）（CD22 0 Jurkat，在低剂量下均处于非活动状态）。在用于抗HER2的ADC在方正5体内抗肿瘤功效与肿瘤停滞观察到0.5-1毫克/千克，1毫克/千克，和3-6毫克/公斤为6，8，和7，分别。对于WSU-DLCL2中的抗CD22 6，观察到2 mg / kg的肿瘤停滞。总之，不可裂解的PBD-ADC具有强大的活性，特别是在HER2模型中。
更新日期：2017-11-17
中文翻译：
吡咯并苯二氮杂二聚体抗体-药物缀合物：不可裂解的药物接头的合成和评价。
通过中间体19合成了三个经过合理设计的吡咯并苯并二氮杂卓（PBD）药物接头，用于抗体-药物偶联物（ADC）。它们在接头中缺乏可裂解的触发物，由用于半胱氨酸抗体偶联的顺丁烯二酰亚胺，亲水性间隔基以及与PBD的炔烃（6），三唑（7）或哌嗪（8）相连。抗HER2 ADC的HER2 3+ SK-BR-3和KPL-4（7个未激活）的体外IC 50值为11–48 ng / mL ，0.12–1.73μg/ mL是HER2 0+ MCF7，全部不激活（7抗CD22 ADC的CD22 3+ BJAB和WSU-DLCL2中处于非活动状态）（CD22 0 Jurkat，在低剂量下均处于非活动状态）。在用于抗HER2的ADC在方正5体内抗肿瘤功效与肿瘤停滞观察到0.5-1毫克/千克，1毫克/千克，和3-6毫克/公斤为6，8，和7，分别。对于WSU-DLCL2中的抗CD22 6，观察到2 mg / kg的肿瘤停滞。总之，不可裂解的PBD-ADC具有强大的活性，特别是在HER2模型中。
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