当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Pyrrolobenzodiazepine Dimer Antibody-Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers.

Pyrrolobenzodiazepine Dimer Antibody-Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers.

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Gregson SJ,Masterson LA,Wei B,Pillow TH,Spencer SD,Kang GD,Yu SF,Raab H,Lau J,Li G,Lewis Phillips GD,Gunzner-Toste J,Safina BS,Ohri R,Darwish M,Kozak KR,Dela Cruz-Chuh J,Polson A,Flygare JA,Howard PW

doi

10.1021/acs.jmedchem.7b00736

subject

Has Abstract

pub_date

2017-12-14 00:00:00

pages

9490-9507

issue

23

eissn

0022-2623

issn

1520-4804

journal_volume

60

pub_type

杂志文章

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