Inducing Proximity: An Emerging Paradigm for New Therapeutic Modalities
Inducing Proximity: An Emerging Paradigm for New Therapeutic Modalities
批准号:
10701073
负责人:
CRAIG M CREWS
金额:
$89.87万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
未结题
起止时间:
2015-09-09 至 2029-08-31
关键词:
AcademiaAddressCell Culture TechniquesClinicalClinical TrialsDevelopmentDiseaseDrug IndustryDrug TargetingDrug usageFDA approvedFutureGenomicsMalignant neoplasm of prostateModalityMultiple MyelomaNuclear Hormone ReceptorsOncogenicOncologyOncoproteinsPharmaceutical PreparationsPharmacologic SubstancePhasePlayProteasome InhibitorProteinsProteolysisRefractoryRelapseResearchSmall Interfering RNATechnologyTranslatingValidationWorkbench to bedsidedrug candidatedrug developmentfirst-in-humanin vivoinnovationknock-downmalignant breast neoplasmnovelnovel anticancer drugnovel drug classnovel therapeuticsprotein degradationproteostasisrecruitsmall moleculesuccesstranslational cancer researchtumorubiquitin-protein ligasewasting
中文摘要
制药行业正处于危机之中;不幸的是,后基因组时代并没有显着改变
制药公司追求的蛋白质数量。由于缺乏新的抗癌药物靶点,
在太多的“我也是”的药物和浪费的努力。为了满足这一需求,我的实验室专注于开发
“受控蛋白质平衡”的新领域。我们最初的努力集中在抑制蛋白质周转;我们
开发了一种新的蛋白酶体抑制剂YU101,作为新的肿瘤学基础
来自我实验室的BioPharma,Proteolix,Inc.最终,YU101成为carfilzomib/Kyprolis®,这是
FDA于2012年批准用于复发/难治性多发性骨髓瘤。最近,我的实验室
专注于蛋白质周转的另一面,即开发一种与siRNA类似的小分子来诱导
蛋白质击倒。我们已经证明了这种策略,即针对嵌合体的蛋白质分解
(PROTACs)可以有效地将靶向癌蛋白招募到E3泛素连接酶以诱导降解,
无论是在细胞培养还是在体内。在目前的R35的过去六年里,我与
我创立的另一家生物制药公司Arvinas,Inc.将这种方法应用于核激素受体
肿瘤学。Arvinas公司的两种基于PROTAC的候选药物(针对前列腺和乳腺的AR和ER
癌症)在首次人类临床试验中被证明减少了它们的目标蛋白,
从而验证了我们的PROTAC技术。在下一个R35阶段,我建议开发这项技术
进一步通过鉴定关键的可降解致癌驱动蛋白和通过开发
肿瘤选择性的PROTACs。此外,PROTACs的临床验证支持
其他基于异双功能化合物的新治疗方式,这些化合物同时包含多种
细胞内的机器。这些创新的方法有可能成为新药开发
通过极大地扩展蛋白质类别可以产生重大影响的范例
以药物为目标。最后,在过去的26年里,我一直专注于将我实验室的研究成果转化为
既有专注于肿瘤学的新企业,也有FDA批准的药物,从而展示了真正的“从工作台到工作台”
床边的研究,这在今天的学术界并不常见。这一创新和执行的记录
在转化型癌症研究中,对未来继续取得成功有很强的预测性。
英文摘要
The pharmaceutical industry is in a crisis; unfortunately the post-genomic era has not significantly changed
the number of proteins pursued by drug companies. This dearth of new cancer drug targets has resulted
in too many ‘me too’ drugs and wasted effort. To address this need, my lab has focused on developing
the new field of ‘Controlled Proteostasis’. Our initial efforts focused on inhibiting protein turnover; we
developed a novel proteasome inhibitor, YU101, which served as the basis of a new oncology-based
biopharma, Proteolix, Inc. from my lab. Ultimately, YU101 became carfilzomib/Kyprolis®, which was
approved by the FDA in 2012 for relapsed/refractory multiple myeloma. More recently, my lab has been
focused on the flipside of protein turnover, i.e., developing a small molecule analogy to siRNA to induce
protein knockdown. We have shown that this strategy, known as Proteolysis Targeting Chimerae
(PROTACs) can effectively recruit targeted oncoproteins to E3 ubiquitin ligases for induced degradation,
both in cell culture and in vivo. Over the past six years of the current R35, I have worked closely with
another biopharma that I founded, Arvinas, Inc., to apply this approach to nuclear hormone receptors in
oncology. Arvinas’ two PROTAC-based drug candidates (targeting AR and ER, for prostate and breast
cancers, respectively) have been shown to decrease their target proteins in first-in-human clinical trials,
thus validating our PROTAC technology. In the next R35 phase, I propose to develop this technology
further through the identification of key degradable oncogenic driver proteins and through the development
of tumor-selective PROTACs. Moreover, the clinical validation of PROTACs supports the development of
additional novel therapeutic modalities based on heterobifunctional compounds that co-opt various
intracellular machineries. These innovative approaches have the potential to be new drug development
paradigms that could have a significant impact by dramatically expanding the protein classes one can
target pharmaceutically. Finally, for the past 26 years, I have focused on translating research from my lab
into both new oncology-focused ventures and a FDA-approved drug, thus demonstrating truly ‘bench-to-
bedside’ research that is not common in academia today. This track record of innovation and execution
within translational cancer research are strong predictors of continued future success.
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DOI:
10.1158/0008-5472.can-18-2918
发表时间:
2019-01-01
期刊:
Cancer research
影响因子:
11.2
作者:
[Hines J, Lartigue S, Dong H, Qian Y, Crews CM]
通讯作者:
Crews CM
DOI:
10.1002/cmdc.201800271
发表时间:
2018-08-10
期刊:
ChemMedChem
影响因子:
3.4
作者:
[Burslem GM, Ottis P, Jaime-Figueroa S, Morgan A, Cromm PM, Toure M, Crews CM]
通讯作者:
Crews CM
DOI:
10.1039/d1cb00011j
发表时间:
2021-03-19
期刊:
RSC chemical biology
影响因子:
4.1
作者:
[Bond MJ, Crews CM]
通讯作者:
Crews CM
DOI:
10.1021/acschembio.1c00693
发表时间:
2021-12-17
期刊:
ACS CHEMICAL BIOLOGY
影响因子:
4
作者:
[Chen, Po-Han, Hu, Zhenyi, An, Elvira, Okeke, Ifunanya, Zheng, Sijin, Luo, Xuanmeng, Gong, Angela, Jaime-Figueroa, Saul, Crews, Craig M.]
通讯作者:
Crews, Craig M.
DOI:
10.1016/j.chembiol.2020.07.020
发表时间:
2020-08-20
期刊:
CELL CHEMICAL BIOLOGY
影响因子:
8.6
作者:
[Nalawansha, Dhanusha A., Crews, Craig M.]
通讯作者:
Crews, Craig M.
共 23 条
Developing Tumor-specific PROTACs
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批准号:10244943
-
项目类别:
-
资助金额:$38.22万
-
财政年份:2019
-
负责人:CRAIG M CREWS
-
依托单位:
Developing Tumor-specific PROTACs
-
批准号:10470405
-
项目类别:
-
资助金额:$37.44万
-
财政年份:2019
-
负责人:CRAIG M CREWS
-
依托单位:
Inducing Proximity: An Emerging Paradigm for New Therapeutic Modalities
-
批准号:10518541
-
项目类别:
-
资助金额:$89.31万
-
财政年份:2015
-
负责人:CRAIG M CREWS
-
依托单位:
Inducing Protein Degradation: A New Pharmaceutical Paradigm
-
批准号:9142301
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项目类别:
-
资助金额:$89.35万
-
财政年份:2015
-
负责人:CRAIG M CREWS
-
依托单位:
Inducing Protein Degradation: A New Pharmaceutical Paradigm
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批准号:10250394
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项目类别:
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资助金额:$87.75万
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财政年份:2015
-
负责人:CRAIG M CREWS
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依托单位:
KRas Ligand Development
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批准号:9023184
-
项目类别:
-
资助金额:$21.78万
-
财政年份:2015
-
负责人:CRAIG M CREWS
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依托单位:
Inducing Protein Degradation: A New Pharmaceutical Paradigm
-
批准号:9763483
-
项目类别:
-
资助金额:$85.11万
-
财政年份:2015
-
负责人:CRAIG M CREWS
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依托单位:
Inducing Protein Degradation: A New Pharmaceutical Paradigm
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批准号:8955987
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项目类别:
-
资助金额:$84.99万
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财政年份:2015
-
负责人:CRAIG M CREWS
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依托单位:
Towards Mammalian Limb Regeneration
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批准号:8536848
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项目类别:
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资助金额:$31.81万
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财政年份:2010
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负责人:CRAIG M CREWS
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依托单位:
Towards Mammalian Limb Regeneration
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批准号:7994509
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项目类别:
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资助金额:$31.52万
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财政年份:2010
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负责人:CRAIG M CREWS
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依托单位:
Towards Mammalian Limb Regeneration
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批准号:8288394
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项目类别:
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资助金额:$0.3万
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财政年份:2010
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负责人:CRAIG M CREWS
-
依托单位:
Towards Mammalian Limb Regeneration
-
批准号:8322068
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项目类别:
-
资助金额:$33.22万
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财政年份:2010
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负责人:CRAIG M CREWS
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依托单位:
Towards Mammalian Limb Regeneration
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批准号:8134803
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项目类别:
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资助金额:$33.58万
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财政年份:2010
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负责人:CRAIG M CREWS
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依托单位:
A MULTIPRONGED, PROTEIN DEGRADATION-BASED APPROACH TO INHIBIT HIV TRANSMISSION
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批准号:7737777
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项目类别:
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资助金额:$46.68万
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财政年份:2009
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负责人:CRAIG M CREWS
-
依托单位:
A MULTIPRONGED, PROTEIN DEGRADATION-BASED APPROACH TO INHIBIT HIV TRANSMISSION
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批准号:7940837
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项目类别:
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资助金额:$46.13万
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财政年份:2009
-
负责人:CRAIG M CREWS
-
依托单位:
A MULTIPRONGED, PROTEIN DEGRADATION-BASED APPROACH TO INHIBIT HIV TRANSMISSION
-
批准号:8306916
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项目类别:
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资助金额:$45.93万
-
财政年份:2009
-
负责人:CRAIG M CREWS
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依托单位:
Predoctoral Training at the Interface Chemistry and Biology
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批准号:7887070
-
项目类别:
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资助金额:$8.7万
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财政年份:2009
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负责人:CRAIG M CREWS
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依托单位:
A MULTIPRONGED, PROTEIN DEGRADATION-BASED APPROACH TO INHIBIT HIV TRANSMISSION
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批准号:8125128
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项目类别:
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资助金额:$45.94万
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财政年份:2009
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负责人:CRAIG M CREWS
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依托单位:
Analysis of Tumorigenic Signaling Pathways with PROTACS
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批准号:7691393
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项目类别:
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资助金额:$29.44万
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财政年份:2006
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负责人:CRAIG M CREWS
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依托单位:
Analysis of Tumorigenic Signaling Pathways with PROTACS
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批准号:7689486
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项目类别:
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资助金额:$28.58万
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财政年份:2006
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负责人:CRAIG M CREWS
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依托单位:
海外基金