Optimization of Potent Ligands for the E3 Ligase DCAF15 and Evaluation of Their Use in Heterobifunctional Degraders

被引：3

作者：

Lucas, Simon C. C. ^{[1
]}

Ahmed, Afshan ^{[2
]}

Ashraf, S. Neha ^{[2
]}

Argyrou, Argyrides ^{[2
]}

Bauer, Matthias R. ^{[1
]}

De Donatis, Gian Marco ^{[2
]}

Demanze, Sylvain ^{[3
]}

Eisele, Frederik ^{[4
]}

Fusani, Lucia ^{[1
]}

Hock, Andreas ^{[2
]}

Kadamur, Ganesh ^{[5
]}

Li, Shuyou ^{[6
]}

Macmillan-Jones, Abigail ^{[2
]}

Michaelides, Iacovos N. ^{[1
]}

Phillips, Christopher ^{[5
]}

Rehnstrom, Marie ^{[7
]}

Richter, Magdalena ^{[2
]}

Rodrigo-Brenni, Monica C. ^{[8
]}

Shilliday, Fiona ^{[5
]}

Wang, Peng ^{[6
]}

Storer, R. Ian ^{[1
]}

机构：

[1] AstraZeneca, Hit Discovery, Discovery Sci, R&D, Cambridge CB2 0AA, England

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

[3] AstraZeneca, Oncol Chem, Oncol R&D, Cambridge CB2 0AA, England

[4] AstraZeneca, Mechanist & Struct Biol, Discovery Sci, R&D, SE-43183 Gothenburg, Sweden

[5] AstraZeneca, Mechanist & Struct Biol, Discovery Sci, R&D, Cambridge CB2 0AA, England

[6] Pharmaron Beijing Co Ltd, Beijing 100176, Peoples R China

[7] Discovery Biol, Discovery Sci, AstraZeneca, R&D, SE-43183 Gothenburg, Sweden

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 07期

关键词：

SULFONAMIDE ANTICANCER AGENT; SELECTIVE DEGRADATION; RBM39; RECRUITMENT; STRUCTURAL BASIS; PHASE-I; INHIBITOR; E7070; EXPRESSION; REAGENTS; PROTACS;

D O I：

10.1021/acs.jmedchem.3c02136

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Unlocking novel E3 ligases for use in heterobifunctional PROTAC degraders is of high importance to the pharmaceutical industry. Over-reliance on the current suite of ligands used to recruit E3 ligases could limit the potential of their application. To address this, potent ligands for DCAF15 were optimized using cryo-EM supported, structure-based design to improve on micromolar starting points. A potent binder, compound 24, was identified and subsequently conjugated into PROTACs against multiple targets. Following attempts on degrading a number of proteins using DCAF15 recruiting PROTACs, only degradation of BRD4 was observed. Deconvolution of the mechanism of action showed that this degradation was not mediated by DCAF15, thereby highlighting both the challenges faced when trying to expand the toolbox of validated E3 ligase ligands for use in PROTAC degraders and the pitfalls of using BRD4 as a model substrate.

引用

页码：5538 / 5566

页数：29

共 37 条

[21] Ubiquitin E3 Ligase CRL4CDT2/DCAF2 as a Potential Chemotherapeutic Target for Ovarian Surface Epithelial Cancer
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Zhou, Jian-Jie
Yu, Chao
Xu, Ying
Guo, Lian-Jun
Zhang, Hai-Yi
Zhou, Dawang
Song, Fang-Zhou
Fan, Heng-Yu
JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (41) : 29680 - 29691
[22] SCFJFK is a bona fide E3 ligase for ING4 and a potent promoter of the angiogenesis and metastasis of breast cancer
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Si, Wenzhe
Chen, Zhe
Li, Lei
Xie, Guojia
Li, Wanjin
Wang, Peiyan
Lei, Liandi
Zhang, Hongquan
Pei, Fei
Cao, Dengfeng
Sun, Luyang
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[23] HIV-1 Vpr activates host CRL4-DCAF1 E3 ligase to degrade histone deacetylase SIRT7
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[24] The CRL4DCAF6 E3 ligase ubiquitinates CtBP1/2 to induce apoptotic signalling and promote intervertebral disc degeneration
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[25] Determinants of lentiviral Vpx-CRL4 E3 ligase-mediated SAMHD1 degradation in the substrate adaptor protein DCAF1
Guo, Haoran
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[26] A synthetic KLHL20 ligand to validate CUL3KLHL20 as a potent E3 ligase for targeted protein degradation
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Yang, Cheng-Hao R.
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[27] The CRL4VPRBP(DCAF1) E3 ubiquitin ligase directs constitutive RAG1 degradation in a non-lymphoid cell line
Schabla, N. Max
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[28] Ubiquitin Specific Peptidase 15 (USP15) suppresses glioblastoma cell growth via stabilization of HECTD1 E3 ligase attenuating WNT pathway activity
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Bady, Pierre
Hegi, Monika E.
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[29] NRIP/DCAF6 stabilizes the androgen receptor protein by displacing DDB2 from the CUL4A-DDB1 E3 ligase complex in prostate cancer
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Fan, Ping
Chang, Szu-Wei
Tsao, Yeou-Ping
Huang, Hsiang-Po
Chen, Show-Li
ONCOTARGET, 2017, 8 (13) : 21501 - 21515
[30] E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia
Chen, Bill B.
Coon, Tiffany A.
Glasser, Jennifer R.
Zou, Chunbin
Ellis, Bryon
Das, Tuhin
McKelvey, Alison C.
Rajbhandari, Shristi
Lear, Travis
Kamga, Christelle
Shiva, Sruti
Li, Chenjian
Pilewski, Joseph M.
Callio, Jason
Chu, Charleen T.
Ray, Anuradha
Ray, Prabir
Tyurina, Yulia Y.
Kagan, Valerian E.
Mallampalli, Rama K.
CELL REPORTS, 2014, 7 (02): : 476 - 487

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