Chemical Biology-Based Tools to Uncover the Function of PARP16 in cancer
基于化学生物学的工具揭示 PARP16 在癌症中的功能
基本信息
- 批准号:10750279
- 负责人:
- 金额:$ 4.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-17 至 2025-07-16
- 项目状态:未结题
- 来源:
- 关键词:ADP ribosylationAcrylamidesActive SitesAdenosine Diphosphate RiboseAlkynesAutomobile DrivingBindingBinding ProteinsBiological AssayBiologyCell DeathCell SurvivalCellsChemicalsChemistryChimeric ProteinsComparative StudyCysteineDiazomethaneDiseaseDrug TargetingEndoplasmic ReticulumEnvironmentEnzymesExhibitsFDA approvedFamilyGeneticGoalsGrowthHumanHydrogen PeroxideKnock-outLabelLeadLengthLightLinkMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of ovaryMapsMass Spectrum AnalysisMediatingMethodsNicotinamide adenine dinucleotideOncologyPhenotypePhosphotransferasesPhysiologyPoly(ADP-ribose) Polymerase InhibitorPost-Translational Protein ProcessingProcessProtacProtein BiosynthesisProteinsProteomeProteomicsResearch PersonnelRoleSignal TransductionStressTechnologyTestingTranslationsUbiquitinUltraviolet RaysWestern Blottingcancer cellcancer subtypescross reactivitycrosslinkdrug candidateinhibitorinsightinterestknock-downlung cancer cellmembernanomolarnew therapeutic targetnovelparalogous genepomalidomidepre-clinicalpreservationprotein degradationprotein protein interactionproteostasisproteotoxicitysmall cell lung carcinomasmall moleculetandem mass spectrometrytooltumor progressionubiquitin-protein ligaseultraviolet irradiation
项目摘要
PROJECT SUMMARY/ABSTRACT
PARP16, a member of the PARP family of enzymes responsible for carrying out the post-translational
modification known as ADP-ribosylating, is emerging as a novel therapeutic target in two cancer subtypes. In
ovarian cancer, PARP16 was shown to negatively regulate protein translation in order to maintain proteostasis.
Genetic deletion (i.e., knockout or knockdown) of PARP16 resulted in an increase in global protein translation,
forcing ovarian cancer cells to enter a state of proteotoxic stress that ultimately leads to cancer cell death. In
small cell lung cancer (SCLC), PARP16 was identified as an off-target to the recently FDA-approved PARP1
inhibitor, talazoparib, suggesting that the efficacy of talazoparib in SCLC may be due to dual targeting of
PARP1 and PARP16. However, knockdown of PARP16 alone also decreased SCLC viability. Both of these
cancer studies point to PARP16 as actionable oncology target, however, the role of PARP16 catalytic activity
in cancer has not been fully characterized. Our group has recently developed the first cysteine-targeted
covalent PARP inhibitor called DB008, that displays excellent proteome-wide selectivity for PARP16 in the
covalent binding mode. While DB008 inhibits PARP16 catalytic activity with nanomolar potency, neither of the
aforementioned PARP16 knockout/knockdown phenotypes were observed with DB008 treatment in ovarian
cancer and SCLC, suggesting that the non-catalytic activity (i.e., protein-protein interactions) of
PARP16 may regulate protein homeostasis and cancer growth as opposed to PARP16 enzymatic
activity. To test this hypothesis, I aim to develop two novel chemical probes, based on DB008, to evaluate the
non-catalytic functions of PARP16 in cancer. In Aim 1, I will synthesize a PARP16 proteolysis targeting
chimera (PROTAC) that will chemically knockdown PARP16 in ovarian cancer and SCLC. The PARP16
PROTAC will evaluate whether depletion of PARP16 and its protein-protein interactions reduces cancer cell
viability as observed with genetic knockdown methods. Completion of this aim will validate PARP16 as a new
cancer target and provide a lead preclinical drug candidate. In Aim 2, I introduce a novel proximity labeling
strategy for identifying interactors of endogenous PARP16 in cancer. This is done by converting DB008 into a
caged photo-crosslinkable probe that uses UV light to uncage and release a reactive crosslinking species that
will covalently tag interacting proteins, which can then be enriched using click chemistry and identified by mass
spectrometry. Completion of this aim will provide understanding for how PARP16 regulates translation and cell
viability in cancer. The technology described in Aim 2 presents a new use case for covalent inhibitors that is
generalizable to other enzymes families beyond PARPs. In summary, this proposal will generate invaluable
chemical biology tools for uncovering the mechanism of action of PARP16 in cancer while also providing a
potential lead drug candidate for combating PARP16-mediated diseases.
项目总结/文摘
项目成果
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- 批准号:
14550841 - 财政年份:2002
- 资助金额:
$ 4.77万 - 项目类别:
Grant-in-Aid for Scientific Research (C)