Discovery of a Novel Benzodiazepine Series of Cbl-b Inhibitors for the Enhancement of Antitumor Immunity

被引：6

作者：

Boerth, Jeffrey A. ^{[1
]}

Chinn, Alex J. ^{[1
]}

Schimpl, Marianne ^{[2
]}

Bommakanti, Gayathri ^{[3
]}

Chan, Christina ^{[4
]}

Code, Erin L. ^{[5
]}

Giblin, Kathryn A. ^{[6
]}

Gohlke, Andrea ^{[2
]}

Hansel, Catherine S. ^{[2
]}

Jin, Meizhong ^{[1
]}

Kavanagh, Stefan L. ^{[7
]}

Lamb, Michelle L. ^{[1
]}

Lane, Jordan S. ^{[2
]}

Larner, Carrie J. B. ^{[7
]}

Mfuh, Adelphe M. ^{[1
]}

Moore, Rachel K. ^{[8
]}

Puri, Taranee ^{[1
]}

Quinn, Taylor R. ^{[1
]}

Ye, Minwei ^{[3
]}

Robbins, Kevin J. ^{[1
]}

Gancedo-Rodrigo, Miguel ^{[2
]}

Tang, Haoran ^{[2
]}

Walsh, Jarrod ^{[8
]}

Ware, Jamie ^{[2
]}

Wrigley, Gail L. ^{[6
]}

Reddy, Iswarya Karapa ^{[3
]}

Zhang, Yun ^{[1
]}

Grimster, Neil P. ^{[1
]}

机构：

[1] AstraZeneca, Med Chem, Oncol R&D, Res & Early Dev, Waltham, MA 02451 USA

[2] AstraZeneca, Discovery Ctr, Discovery Sci, R&D, Cambridge CB2 0AA, England

[3] AstraZeneca, Biosci, Oncol R&D, Waltham, MA 02451 USA

[4] AstraZeneca, DMPK, Res & Early Dev, Oncol R&D, Cambridge CB2 0AA, England

[5] AstraZeneca, Discovery Sci, R&D, Waltham, MA 02451 USA

[6] AstraZeneca, Med Chem, Res & Early Dev, Oncol R&D, Cambridge CB2 0AA, England

[7] AstraZeneca, Clin Pharmacol & Safety Sci, R&D, Cambridge CB2 0AA, England

[8] AstraZeneca, R&D BioPharmaceut, Discovery Sci, High Throughput Screening,Hit Discovery, Macclesfield SK10 4TG, England

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2023年 / 14卷 / 12期

关键词：

Cbl-b; T-cell activation; immuno-oncology; benzodiazepines; E3; ligases; T-CELLS; UBIQUITIN; MECHANISMS; AUTOINHIBITION; ACTIVATION; CANCER; INNATE;

D O I：

10.1021/acsmedchemlett.3c00439

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that is responsible for repressing T-cell, natural killer (NK) cell, and B-cell activation. The robust antitumor activity observed in Cbl-b deficient mice arising from elevated T-cell and NK-cell activity justified our discovery effort toward Cbl-b inhibitors that might show therapeutic promise in immuno-oncology, where activation of the immune system can drive the recognition and killing of cancer cells. We undertook a high-throughput screening campaign followed by structure-enabled optimization to develop a novel benzodiazepine series of potent Cbl-b inhibitors. This series displayed nanomolar levels of biochemical potency, as well as potent T-cell activation. The functional activity of this class of Cbl-b inhibitors was further corroborated with ubiquitin-based cellular assays.

引用

页码：1848 / 1856

页数：9

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