A platform to identify in vivo targets of covalent cancer drugs in 3D tissues
A platform to identify in vivo targets of covalent cancer drugs in 3D tissues
批准号:
10714543
负责人:
BENJAMIN F CRAVATT
金额:
$45.07万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-19 至 2026-08-31
关键词:
3-DimensionalAccelerationAdoptedAffinityAgammaglobulinaemia tyrosine kinaseAnimalsAntineoplastic AgentsAspirinBindingBrainCardiotoxicityCardiovascular systemCellsChemicalsChemistryClinicalCommunitiesDataDevelopmentDoseDrug TargetingDrug or chemical Tissue DistributionDrug toxicityEnsureEnzyme Inhibitor DrugsEnzymesEpidermal Growth Factor ReceptorFAAH inhibitorFibroblast Growth Factor ReceptorsFluorescenceFoundationsFrightFutureGoalsHeartHistologicHumanHybridsImageIn SituJAK3 geneKRAS2 geneKnowledgeLabelLinkMalignant NeoplasmsMammalsMapsMethodsModelingMolecularMusNatureNeuronsOncogenicOncologyOrganOrganismPenicillinsPersonsPharmaceutical PreparationsPhosphotransferasesPositron-Emission TomographyPrognosisProteinsProteomicsProtocols documentationRecording of previous eventsResolutionSignal TransductionSpecificityStructureStructure-Activity RelationshipTechniquesTechnologyTherapeutic IndexThinnessTissue imagingTissuesToxic effectTranslationsTyrosine Kinase Inhibitorbody systembropiriminecancer therapycell typecellular targetingchemoproteomicsdata streamsdesigndrug discoveryfallshigh resolution imagingimaging approachimaging modalityin vivoin vivo imaginginhibitorinterestkinase inhibitorlead optimizationpreferenceprogramsscale upscreeningside effectsmall moleculesuccesstechnology developmenttoolwhole body imaging
中文摘要
摘要
英文摘要
Abstract
Covalent inhibitors represent some of the most successful drugs in human history, including aspirin and
penicillin. Recently, targeted covalent drugs have taken center stage as a compelling approach for achieving
major goals in oncology that have proven elusive for more classical reversible small molecules, including, for
instance, the selective inactivation of oncogenic kinases (BTK, EGFR, FGFR, JAK3) and, most notably, the
inhibition of the once-deemed undruggable KRAS protein. We are now in the midst of a resurgence of interest
in covalent drugs for their demonstrated capability to engage cancer targets that have been historically
considered undruggable. However, despite their proven success and inherent advantages of potency, there
has been a general reluctance to develop covalent drugs due to the concern of potential irreversible off-target
toxicity across different organ systems. Hence, a comprehensive understanding of both on and off-targets in
vivo is critical for covalent drugs. Currently, it is impossible to determine drug binding across a whole animal
with cellular and molecular resolution in mammals.
Building upon a recent breakthrough in tissue imaging termed CATCH (Clearing-Assisted Tissue click
Chemistry), we propose to develop a general platform for in vivo imaging of drug-target interactions with
unprecedented spatial precision by integrated applications of high-resolution whole-body imaging and
chemoproteomics (such as Activity-Based Proteomic Profiling, or ABPP) through the same covalent probes.
This way, every cell in a living mammal targeted by the drug (both on- and off-target) can be revealed in situ
and registered onto a defined protein map to screen and identify in vivo drug targets. The data stream
generated by this platform could rapidly link the rich knowledge of drug affinity to the therapeutic index,
therefore accelerating the translation of chemical activities into cancer therapies.
Our team has well-established and complementary expertise in chemoproteomics and tissue imaging to
ensure the successful execution of the project. In this IMAT R33 application, we plan to further develop
CATCH to profile in vivo targets of covalent kinase inhibitors. First, we will adapt CATCH to 3D somatic tissues
(Aim 1). Next, we will expand CATCH to an array of covalent BTK (Bruton’s tyrosine kinase) inhibitors (Aim 2).
Finally, we will profile dose-dependent in vivo cellular targets of BTK inhibitors in the mouse cardiovascular
system (Aim 3). We anticipate that these studies will establish in vivo CATCH methods for identifying targets of
covalent BTK inhibitors to better understand their efficacy and toxicity. More generally, the established platform
can be broadly applied to any covalent cancer drug for unbiased in vivo target identification. The pipeline,
analytics, and high-resolution drug target data will be rapidly disseminated for public access and exploration,
releasing an immediate, direct, and profound impact on covalent cancer drug discovery and refinement.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
eDyNAmiC - SCRIPPS
-
批准号:10625797
-
项目类别:
-
资助金额:$33.23万
-
财政年份:2022
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
eDyNAmiC - SCRIPPS
-
批准号:10845774
-
项目类别:
-
资助金额:$33.45万
-
财政年份:2022
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Integrated ligand and target discovery by chemical proteomics for glioblastoma treatment.
-
批准号:10652580
-
项目类别:
-
资助金额:$66.69万
-
财政年份:2021
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Integrated ligand and target discovery by chemical proteomics for glioblastoma treatment.
-
批准号:10436295
-
项目类别:
-
资助金额:$67.19万
-
财政年份:2021
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Integrated ligand and target discovery by chemical proteomics for glioblastoma treatment.
-
批准号:10211553
-
项目类别:
-
资助金额:$69.66万
-
财政年份:2021
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
RP5: Chemical proteomic discovery of small-molecule probes for autophagy proteins
-
批准号:10364727
-
项目类别:
-
资助金额:$167.24万
-
财政年份:2019
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
RP5: Chemical proteomic discovery of small-molecule probes for autophagy proteins
-
批准号:10573265
-
项目类别:
-
资助金额:$172.91万
-
财政年份:2019
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Chemical Proteomic Platforms for Radically Expanding Cancer Druggability
-
批准号:10248401
-
项目类别:
-
资助金额:$116.1万
-
财政年份:2018
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Chemical Proteomic Platforms for Radically Expanding Cancer Druggability
-
批准号:10477261
-
项目类别:
-
资助金额:$113.78万
-
财政年份:2018
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Chemical Proteomic Platforms for Radically Expanding Cancer Druggability
-
批准号:10693197
-
项目类别:
-
资助金额:$113.78万
-
财政年份:2018
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Chemoproteomic Identification and Therapeutic Validation of Proteins of Metabolic Significance
-
批准号:9753226
-
项目类别:
-
资助金额:$164.06万
-
财政年份:2017
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Chemoproteomic Identification and Therapeutic Validation of Proteins of Metabolic Significance
-
批准号:10220956
-
项目类别:
-
资助金额:$164.06万
-
财政年份:2017
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Chemoproteomic Identification and Therapeutic Validation of Proteins of Metabolic Significance
-
批准号:9380300
-
项目类别:
-
资助金额:$168.73万
-
财政年份:2017
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
High-Throughput screening for inhibitors of neuroinflammatory lipid production
-
批准号:9104860
-
项目类别:
-
资助金额:$49.33万
-
财政年份:2016
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
High-Throughput screening for inhibitors of neuroinflammatory lipid production
-
批准号:9222811
-
项目类别:
-
资助金额:$38.27万
-
财政年份:2016
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Chemical Approaches for Activity-Based Proteomics
-
批准号:9021605
-
项目类别:
-
资助金额:$29.48万
-
财政年份:2014
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Chemical Approaches for Activity-Based Proteomics
-
批准号:8803892
-
项目类别:
-
资助金额:$29.48万
-
财政年份:2014
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Identification and Therapeutic Valiation of Adipocyte Serine Hydrolases of Metab
-
批准号:9143096
-
项目类别:
-
资助金额:$138.41万
-
财政年份:2013
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Identification and Therapeutic Valiation of Adipocyte Serine Hydrolases of Metab
-
批准号:8583477
-
项目类别:
-
资助金额:$86.5万
-
财政年份:2013
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
Identification and Therapeutic Valiation of Adipocyte Serine Hydrolases of Metab
-
批准号:8721954
-
项目类别:
-
资助金额:$108.99万
-
财政年份:2013
-
负责人:BENJAMIN F CRAVATT
-
依托单位:
海外基金