Small Molecule E6 Inhibitors to Treat Oropharyngeal Cancers Caused by HPV Infections
小分子 E6 抑制剂治疗 HPV 感染引起的口咽癌
基本信息
- 批准号:10484043
- 负责人:
- 金额:$ 27.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAnatomyAnimalsAntiviral AgentsApoptosisAttentionBindingBiochemicalBiologicalBiological AssayCancer EtiologyCell LineCellsClinicalComplexCoupledCrystallizationCysteineDNADataDockingDoseDrug KineticsDysplasiaEtiologyFormulationFrequenciesGoalsGrantHIVHPV oropharyngeal cancerHumanHuman Papilloma Virus VaccineHuman Papilloma Virus-Related Malignant NeoplasmHuman PapillomavirusHuman papilloma virus infectionHuman papillomavirus 16Immunodeficient MouseIn VitroIncidenceIndividualInfectionLeadLesionLiver MicrosomesLocalesMaintenanceMalignant NeoplasmsMalignant Vaginal NeoplasmMalignant neoplasm of anusMalignant neoplasm of cervix uteriMalignant neoplasm of vulvaMediatingMedicalMicrosomesModelingMorbidity - disease rateMusNeoplastic Cell TransformationOncogenicOncoproteinsOperative Surgical ProceduresOralOropharyngealPapillomavirus Transforming Protein E6PatientsPharmaceutical ChemistryPharmaceutical PreparationsPharmacotherapyPhasePositioning AttributePropertyProteinsProtocols documentationRadiation therapyRegimenReportingSafetySiteSmall Business Innovation Research GrantSolubilitySpecificitySwabTP53 geneTechnologyTestingTherapeuticToxic effectTumor Suppressor ProteinsUBE3A geneUbiquitinUbiquitinationValidationViral GenomeVirus DiseasesVirus InhibitorsWomanX-Ray CrystallographyXenograft Modeladductantiviral drug developmentaqueousbasecancer cellcellular targetingcovalent bonddesignexperimental studyhigh riskin silicoin vitro activityin vivoin vivo Modelin vivo evaluationinhibitormalignant mouth neoplasmmalignant oropharynx neoplasmmenmortalitymulticatalytic endopeptidase complexnoveloral HPVpharmacokinetic modelpopulation surveypreventprophylacticprotein protein interactionprototyperesponsescaffoldscreeningsmall moleculesmall molecule librariesstandard of caretumortumor growthtumor xenograftubiquitin ligase
项目摘要
Oncogenic human papillomaviruses (HPV) such as HPV type 16 are the etiologic agent of 50-70% of cancers
of the oropharynx. In the USA, the incidence of HPV-associated oropharyngeal cancers is increasing. This is
partly because there is no established screening test for oral HPV. HPV-16 DNA is detected by PCR in 1-8% of
oral swabs depending on the surveyed populations, with the highest frequencies in HIV+ individuals. Only a
small fraction of these infections will progress to frank malignancy. Moreover, early lesions are difficult to locate
and patients are largely asymptomatic until they have advanced tumors.
Kovina Therapeutics is developing anti-viral therapeutics that selectively bind to the HPV-16 E6 oncoprotein
and prevent interactions with its cellular targets. E6 is necessary for viral genome replication and maintenance
and is always expressed in HPV-associated dysplasia and malignancies. We performed in silico structural
screening of chemical libraries for molecules that fit the E6 docking site for several of its cellular partners. Our
assays focused on the E6 protein-protein interaction with E6AP, which transfers ubiquitin onto the tumor
suppressor protein p53 and leads to its destruction by the proteasome. We designed and synthesized
compounds that 1) bind to HPV-16 E6 and 2) form a covalent bond with a specific cysteine in HPV-16 E6 at its
protein-protein interface with E6AP as well as other cellular interacting proteins. The approach to identify
molecules equipped with reactive ‘warheads’ that mediate covalent and irreversible binding to cysteine has been
successful for several new clinically available drugs, and this field is rapidly progressing to target proteins that
were previously considered undruggable. We show that these compounds covalently bind to HPV-16 E6, block
E6 interaction with E6AP, restore P53 function, and drive the HPV infected cell to apoptosis. Multiple biochemical
analyses including X-ray crystallography prove these inhibitors occupy this E6 pocket and form a single adduct
with this cysteine. Iterative optimization guided by the co-crystal data resulted in the design and synthesis of
>200 novel chemotypes that resulted in increased activity. This one-year Phase I SBIR proposal will select leads
based on for pharmacokinetic characterization. The most promising E6 inhibitors will then be test in vivo proof
of concept experiments using human oropharyngeal cancer derived cells in a tumor xenograft model. Successful
results in these Phase I experiments will strongly position us for a Phase II SBIR grant to carry out IND-enabling
studies.
致癌性人乳头瘤病毒(HPV)如HPV 16型是50-70%癌症的病原体
口咽部在美国,HPV相关口咽癌的发病率正在增加。这是
部分原因是没有建立口腔HPV的筛查测试。HPV-16 DNA通过PCR在1-8%的
口腔拭子的感染率取决于被调查人群,艾滋病毒阳性者的感染率最高。只有
这些感染中的一小部分将发展为明显的恶性肿瘤。而且,早期病变很难定位
并且患者在患晚期肿瘤之前基本上没有症状。
Kovenant Therapeutics正在开发选择性结合HPV-16 E6癌蛋白的抗病毒治疗剂
并阻止其与细胞靶点的相互作用。E6是病毒基因组复制和维持所必需的
并且总是在HPV相关的异型增生和恶性肿瘤中表达。我们进行了计算机结构分析,
筛选化学文库中适合E6对接位点的分子,用于其几种细胞伴侣。我们
分析集中在E6蛋白与E6 AP的相互作用,E6 AP将泛素转移到肿瘤上
抑制蛋白p53,并导致其被蛋白酶体破坏。我们设计合成了
化合物1)结合HPV-16 E6和2)与HPV-16 E6中的特异性半胱氨酸在其
与E6 AP以及其他细胞相互作用蛋白质的蛋白质-蛋白质界面。识别方法
配备有反应性“弹头”的分子介导了与半胱氨酸的共价和不可逆结合,
成功地用于几种新的临床可用药物,并且该领域正在迅速发展到靶向蛋白质,
以前被认为是不可用的我们表明这些化合物与HPV-16 E6共价结合,阻断HPV-16 E6
E6与E6 AP相互作用,恢复P53功能,驱动HPV感染细胞凋亡。多个生物化学
包括X射线晶体学在内的分析证明这些抑制剂占据了E6口袋并形成单一加合物
这个半胱氨酸。在共晶数据的指导下进行迭代优化,设计和合成了
>200种新的化学型,导致活性增加。这份为期一年的第一阶段SBIR提案将选择潜在客户
基于药代动力学表征。最有前途的E6抑制剂将在体内进行测试证明
在肿瘤异种移植模型中使用人口咽癌衍生细胞的概念实验。成功
这些第一阶段实验的结果将有力地为我们提供第二阶段SBIR拨款,以实现IND
问题研究
项目成果
期刊论文数量(0)
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ELLIOT J. ANDROPHY其他文献
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{{ truncateString('ELLIOT J. ANDROPHY', 18)}}的其他基金
Small Molecule E6 Inhibitors to Treat Dysplasia Caused by HPV Infections
小分子 E6 抑制剂治疗 HPV 感染引起的发育异常
- 批准号:
10390563 - 财政年份:2022
- 资助金额:
$ 27.58万 - 项目类别:
Development of a mouse model to test HPV Antiviral compounds
开发小鼠模型来测试 HPV 抗病毒化合物
- 批准号:
10582890 - 财政年份:2022
- 资助金额:
$ 27.58万 - 项目类别:
Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
小分子共价 E6 拮抗剂治疗 HPV 感染
- 批准号:
10220227 - 财政年份:2021
- 资助金额:
$ 27.58万 - 项目类别:
Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
小分子共价 E6 拮抗剂治疗 HPV 感染
- 批准号:
10397131 - 财政年份:2021
- 资助金额:
$ 27.58万 - 项目类别:
Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
小分子共价 E6 拮抗剂治疗 HPV 感染
- 批准号:
10610388 - 财政年份:2021
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Optimization of a novel series of thiazolopyridines for the treatment of SMA
用于治疗 SMA 的新型噻唑并吡啶系列的优化
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Toward drug treatment of spinal muscular atrophy: Mechanism of action
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10612848 - 财政年份:2013
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