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
基本信息
- 批准号:10390563
- 负责人:
- 金额:$ 29.85万
- 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:2022-07-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAntiviral AgentsAnusApoptosisApplications GrantsAttentionBindingBiochemicalBiologicalBiological AssayCellsCervicalCervix UteriCessation of lifeClinicalCollectionComplexCoupledCreamCrystallizationCysteineDataDrug KineticsDrug TargetingDysplasiaEpithelialEvaluationFormulationGelGenitalGenitaliaGenotypeGoalsGuidelinesHIVHumanHuman Papilloma Virus VaccineHuman PapillomavirusHuman papilloma virus infectionHuman papillomavirus 16In VitroInfectionInfectious Skin DiseasesInflammatory ResponseInvestigationLeadLesionLiver MicrosomesLotionMaintenanceMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of cervix uteriMeasuresMediatingMedicalMolecular WeightMorbidity - disease rateMucous MembraneMusNeoplastic Cell TransformationOintmentsOperative Surgical ProceduresPainPharmaceutical PreparationsPharmacotherapyPhasePopulationPositioning AttributeProceduresProcessPropertyProteinsSafetySeriesSkinSmall Business Innovation Research GrantSmall Molecule Chemical LibrarySolubilitySpecific qualifier valueTP53 geneTestingTherapeuticTopical agentTopical applicationToxic effectToxicologyTumor Suppressor ProteinsUBE3A geneUbiquitinationVaginaViral GenomeVirusVirus DiseasesVulvaWait TimeWomanWorkX-Ray Crystallographyadductbasecancer invasivenesscellular targetingcovalent bonddesigndrug developmentexperimental studyhigh riskin silicoin vivoinhibitorintraepithelialmenmetabolic abnormality assessmentmodel designmodel developmentmulticatalytic endopeptidase complexnovelpharmacokinetic modelphase 1 studypremalignantpreventprophylacticprotein protein interactionprototypescreeningsmall moleculesmall molecule librariesstandard of caresuccesssystemic toxicityubiquitin ligase
项目摘要
Human papillomaviruses (HPV) cause exceedingly common infections of cutaneous and
mucosal epithelia. Infection with specific “high risk” HPV genotypes can progress to pre-
malignant lesions called dysplasias, which over a period of years, can eventuate in invasive and
metastatic epithelial malignancies. Our therapeutic goal is to treat early stage infections of the
cervix, genitalia, and anus that afflict millions of women and men before these progress to invasive
cancers.
Kovina Therapeutics strategy is to eliminate HPV infection by selectively targeting the E6
protein and preventing interactions with its cellular binding partners. E6 is necessary for viral
genome replication and maintenance and is always expressed in HPV-associated dysplasia and
malignancies. We performed in silico screening of chemical libraries for small molecules that
would resemble the interface of E6 with several of its cellular partners. Our assays focused on the
protein-protein interaction of E6 with the ubiquitin ligase E6AP, which mediates ubiquitination and
proteasome mediated destruction of the tumor suppressor protein p53. Using this model, we
designed and synthesized compounds that 1) bind to HPV-16 E6 and 2) are armed with a ‘warhead’
to make a covalent bond with a specific cysteine in HPV-16 E6 binding pocket for E6AP. The
approach to identify molecules equipped with reactive warheads that mediate covalent and
irreversible binding to cysteine is exemplified in several new clinically available drugs that target
proteins previously considered undruggable. We discovered several compounds covalently bound
to E6 via this cysteine residue, block E6 interaction with E6AP, restore P53 function, and induce
death of HPV-16 expressing cells. Multiple biochemical analyses including X-ray crystallography
prove these inhibitors occupy the targeted E6 pocket and form a single adduct with this cysteine.
Iterative optimization guided by the co-crystal data enabled design and synthesis of >80 novel
compounds and has resulted chemotypes with increased activity. This one-year Phase I SBIR
proposal plans to screen our existing E6 inhibitor collection to determine their biological activities
in cell-based assays and pharmacokinetic properties that would meet FDA guidelines for a topical
agent. We will initiate drug development studies including formulation for topical application and
early stage pharmacokinetic and toxicology characterization. The success of Phase I study will
validate this antiviral strategy and position us to proceed to apply for a Phase II SBIR to perform
IND-enabling studies.
人乳头瘤病毒(HPV)引起非常常见的皮肤和
粘膜上皮细胞。感染特定的高危HPV基因型会进展到前
称为异型增生的恶性病变,在一段时间内,可最终发展为侵袭性和
转移性上皮性恶性肿瘤。我们的治疗目标是治疗早期感染的
宫颈、生殖器和肛门,在这些进展到侵入性之前,折磨着数百万的女性和男性
癌症。
Kovina治疗公司的策略是通过选择性地靶向E6来消除HPV感染
蛋白质和阻止与其细胞结合伙伴的相互作用。E6对于病毒来说是必要的
基因组复制和维持,并总是在HPV相关的异型增生和
恶性肿瘤。我们对小分子的化学库进行了电子筛选,
将类似于E6与其几个蜂窝合作伙伴的接口。我们的化验结果集中在
E6与泛素连接酶E6AP的蛋白质-蛋白质相互作用
蛋白酶体介导的肿瘤抑制蛋白P53的破坏。使用这个模型,我们
设计和合成的1)与HPV-16 E6结合的化合物和2)配备了“弹头”
与E6AP的HPV-16E6结合口袋中的特定半胱氨酸形成共价键。这个
识别装备有反应弹头的分子的方法,这些反应弹头调解共价和
与半胱氨酸的不可逆结合在几种新的临床可用药物中得到了例证
以前被认为不能下药的蛋白质。我们发现了几种共价结合的化合物
通过这个半胱氨酸残基,阻断E6与E6AP的相互作用,恢复P53功能,诱导
表达HPV-16的细胞死亡。包括X射线结晶学在内的多种生化分析
证明这些抑制剂占据靶向E6口袋,并与半胱氨酸形成单一加合物。
共晶数据引导下的迭代优化设计与合成>;80新化合物
化合物,并导致化学类型的活性增加。这项为期一年的第一阶段SBIR
提案计划筛选我们现有的E6抑制剂集合,以确定它们的生物活性
在基于细胞的分析和药代动力学特性中,符合FDA的局部应用指南
探员。我们将开展药物开发研究,包括外用配方和
早期药代动力学和毒理学特征。第一阶段研究的成功将
验证此抗病毒策略,并使我们能够继续申请第二阶段SBIR以执行
支持IND的研究。
项目成果
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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 Oropharyngeal Cancers Caused by HPV Infections
小分子 E6 抑制剂治疗 HPV 感染引起的口咽癌
- 批准号:
10484043 - 财政年份:2022
- 资助金额:
$ 29.85万 - 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:
$ 29.85万 - 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:
$ 29.85万 - 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:
$ 29.85万 - 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
- 批准号:
8892548 - 财政年份:2015
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Toward drug treatment of spinal muscular atrophy: Mechanism of action
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8823350 - 财政年份:2014
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The COPA vesicle protein and pathogenesis of spinal muscular atrophy
COPA囊泡蛋白与脊髓性肌萎缩症发病机制
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The Indiana Cutaneous Biological Research Training Program
印第安纳州皮肤生物学研究培训计划
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8827676 - 财政年份:2013
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The COPA vesicle protein and pathogenesis of spinal muscular atrophy
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- 批准号:
10612848 - 财政年份:2013
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$ 29.85万 - 项目类别:
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