Developing novel LOX inhibitors to target chemotherapy resistant TNBC
开发新型 LOX 抑制剂以靶向化疗耐药的 TNBC
基本信息
- 批准号:10696810
- 负责人:
- 金额:$ 40.65万
- 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:2023-06-08 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAntibody-drug conjugatesBenchmarkingBindingBinding ProteinsBiological AssayBiological AvailabilityBiometryBreast Cancer CellBreast Cancer ModelBreast Cancer PatientBreast Cancer cell lineCancer BiologyCanis familiarisCardiotoxicityCell LineCellsCessation of lifeChemoresistanceChemosensitizationCollagenCommunicationComplementDedicationsDoxorubicinDrug KineticsExtracellular MatrixFibronectinsGoalsGrantHypoxiaImmunocompetentImmunologic Deficiency SyndromesImmunotherapyIn VitroInduction of ApoptosisLeadLegal patentLibrariesMammary NeoplasmsMaximum Tolerated DoseMediatorMedical OncologyMetabolicMissionModelingModificationMonoamine OxidaseMusNatureOralOrganoidsOutcomePTK2 genePatientsPenetrationPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPharmacodynamicsPhasePhenotypePhosphotransferasesPlasma ProteinsPropertyProtein-Lysine 6-OxidasePublic HealthReactionResistanceSafetySerum ProteinsSignal TransductionSmall Business Technology Transfer ResearchSolubilitySpecificityStructure-Activity RelationshipTestingTherapeuticTimeToxic effectUnited States National Institutes of Healthaggressive breast cancerbreast surgerycancer subtypescellular targetingchemosensitizing agentchemotherapyclinically relevantcrosslinkdesigndisabilitydrug candidatedrug discoveryeffective therapygenotoxicityimprovedin vitro Assayin vivoinhibitorlead optimizationmRNA Expressionmalignant breast neoplasmmembermetermortalitymouse modelnoveloverexpressionpatient derived xenograft modelpharmacokinetics and pharmacodynamicspharmacophoreprotein expressionscreeningsmall molecule librariessuccesssynergismtherapy resistanttranslational potentialtreatment strategytriple-negative invasive breast carcinomatumor
项目摘要
PROJECT SUMMARY
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It accounts for ~15% of
all breast cancer yet is responsible for 30% of breast cancer deaths. TNBC is treated primarily by conventional
chemotherapy; however, resistance to therapy is common, leading to high mortality rates. Importantly, the
benefit of current therapeutic strategies used in chemoresistant TNBC; i.e., immunotherapy and antibody-
drug conjugates, is confined to only a fraction of patients, and survival benefit is limited. Therefore, there is
an urgent need to identify novel and effective treatment strategies to overcome resistance to chemotherapy.
Recently, we identified hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key mediator of
chemoresistance in TNBC (Saatci et al, Nature Communications, 2020). We showed that LOX is
overexpressed in chemoresistant tumors, and its inhibition re-sensitizes the most aggressive breast tumors
to doxorubicin using several clinically-relevant mouse models. However, the available LOX inhibitors are
either non-selective or has toxicity. Hence, our main objective in this project is to develop potent, specific and
well-tolerated LOX inhibitors to overcome chemoresistance in TNBC that has a high translational potential.
Through high-throughput compound library screening and hit-to-lead conversion studies, we identified
compounds with potent on-target cellular engagement of LOX, with good oral pharmacokinetics (PK) and
with chemosensitizer effect without major toxicity (US PTO 17/693,371 and PCT/US2022/20086, patent
pending). Starting from our current non-optimized lead molecule, we aim to develop lead compounds with
increased potency, safety and drug-likeness. To accomplish this goal, in Phase I of this Fast-Track STTR
grant, we will generate a diverse library of small molecules via an extensive structure activity relationship
(SAR) study using our initial pharmacophore. We will test the synthesized inhibitors with respect to the degree
of LOX enzymatic activity inhibition, LOX binding and selectivity towards LOX. We will perform the off-target
assessment of the inhibitors using CEREP screen as well as kinome profiling. The shortlisted candidates will
further be tested in ECM crosslinking and 3D chemosensitization assays using both cell lines and organoids.
Inhibitors with better efficacy, selectivity and stability will move to Phase II. In Phase II, we will perform several
ADME assays, including metabolic stability/identity, Caco-2 permeability and transport, cardiotoxicity and
genotoxicity, plasma protein binding, CYP inhibition/induction/reaction phenotyping to improve drug-like
properties while maintaining on-target potency in TNBC cells. Detailed PK/PD and toxicity analyses of the
most promising candidates will be carried out followed by testing their chemosensitizer effect using both
state-of-the-art immunodeficient (cell line- and patient-derived xenografts) and immunocompetent
(syngeneic) mice models. The successful completion of the proposed project will lead to potent and specific,
lead-optimized LOX inhibitors to overcome chemoresistance in TNBC, the deadliest form of breast cancer.
项目摘要
三阴性乳腺癌(TNBC)是最具侵袭性的乳腺癌亚型。约占15%,
所有的乳腺癌导致了30%的乳腺癌死亡。TNBC主要通过常规治疗来治疗。
化疗;然而,对治疗的抵抗是常见的,导致高死亡率。重要的是
目前用于化学抗性TNBC的治疗策略的益处;即,免疫疗法和抗体-
药物缀合物仅限于一小部分患者,并且生存益处有限。因此有
迫切需要确定新的和有效的治疗策略,以克服耐药性化疗。
最近,我们确定了缺氧诱导的ECM重塑剂赖氨酰氧化酶(LOX)作为缺氧诱导ECM重塑的关键介质。
(Saatci等,Nature Communications,2020)。我们发现LOX
在化疗耐药肿瘤中过表达,其抑制使最具侵袭性的乳腺肿瘤重新敏感
使用几种临床相关的小鼠模型。然而,可用的LOX抑制剂是
非选择性或具有毒性。因此,我们在这个项目中的主要目标是开发有效的,具体的,
耐受性良好的LOX抑制剂,以克服具有高翻译潜力的TNBC中的化学抗性。
通过高通量化合物库筛选和命中到铅转换研究,我们确定了
具有LOX的有效靶向细胞接合的化合物,具有良好的口服药代动力学(PK),
具有化学增敏作用而无主要毒性(US PTO 17/693,371和PCT/US 2022/20086,专利号1000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000
待定)。从我们目前未优化的先导分子出发,我们的目标是开发具有以下特性的先导化合物:
增加效力、安全性和药物相似性。为了实现这一目标,在本快速通道STTR的第一阶段,
格兰特,我们将通过广泛的结构活性关系产生一个多样化的小分子库
(SAR)使用我们最初的药效团进行研究。我们将测试合成的抑制剂的程度
LOX酶活性抑制、LOX结合和对LOX的选择性。我们将执行脱靶
使用CEREP筛选以及激酶组分析评估抑制剂。入围的候选人将
进一步在ECM交联和3D化学敏化测定中使用细胞系和类器官进行测试。
有效性、选择性和稳定性更好的抑制剂将进入II期。在第二阶段,我们将执行几个
ADME测定,包括代谢稳定性/同一性、Caco-2渗透性和转运、心脏毒性和
遗传毒性、血浆蛋白结合、抑制/诱导/反应表型分析,以改善药物样
在TNBC细胞中保持靶向效力的同时,详细的PK/PD和毒性分析
最有前途的候选人将进行,然后通过测试他们的化疗增敏剂的效果,
最先进的免疫缺陷(细胞系和患者来源的异种移植物)和免疫活性
(同基因)小鼠模型。拟议项目的成功完成将导致有效和具体的,
铅优化LOX抑制剂,以克服TNBC的耐药性,最致命的乳腺癌形式。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Ozgur Sahin其他文献
Ozgur Sahin的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Ozgur Sahin', 18)}}的其他基金
Inhibiting tumor growth and metastasis in highly aggressive breast cancers with centrosome amplification
通过中心体扩增抑制高度侵袭性乳腺癌的肿瘤生长和转移
- 批准号:
10670436 - 财政年份:2022
- 资助金额:
$ 40.65万 - 项目类别:
Inhibiting tumor growth and metastasis in highly aggressive breast cancers with centrosome amplification
通过中心体扩增抑制高度侵袭性乳腺癌的肿瘤生长和转移
- 批准号:
10621529 - 财政年份:2022
- 资助金额:
$ 40.65万 - 项目类别:
Nanomechanical studies of cells and biomolecules
细胞和生物分子的纳米力学研究
- 批准号:
10406574 - 财政年份:2022
- 资助金额:
$ 40.65万 - 项目类别:
Nanomechanical studies of cells and biomolecules
细胞和生物分子的纳米力学研究
- 批准号:
10668957 - 财政年份:2022
- 资助金额:
$ 40.65万 - 项目类别:
Overcoming chemoresistance in triple negative breast cancer
克服三阴性乳腺癌的化疗耐药性
- 批准号:
10345694 - 财政年份:2021
- 资助金额:
$ 40.65万 - 项目类别:
Inhibiting tumor growth and metastasis in highly aggressive breast cancers with centrosome amplification
通过中心体扩增抑制高度侵袭性乳腺癌的肿瘤生长和转移
- 批准号:
10298311 - 财政年份:2021
- 资助金额:
$ 40.65万 - 项目类别:
Overcoming chemoresistance in triple negative breast cancer
克服三阴性乳腺癌的化疗耐药性
- 批准号:
10541879 - 财政年份:2021
- 资助金额:
$ 40.65万 - 项目类别:
Overcoming chemoresistance in triple negative breast cancer
克服三阴性乳腺癌的化疗耐药性
- 批准号:
10642470 - 财政年份:2021
- 资助金额:
$ 40.65万 - 项目类别:
Nanomechanical imaging of protein dynamics via programmable DNA interactions
通过可编程 DNA 相互作用进行蛋白质动力学纳米力学成像
- 批准号:
10020421 - 财政年份:2019
- 资助金额:
$ 40.65万 - 项目类别:
Nanomechanical imaging of protein dynamics via programmable DNA interactions
通过可编程 DNA 相互作用进行蛋白质动力学纳米力学成像
- 批准号:
10217200 - 财政年份:2019
- 资助金额:
$ 40.65万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 40.65万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 40.65万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 40.65万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 40.65万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 40.65万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 40.65万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 40.65万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 40.65万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 40.65万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 40.65万 - 项目类别:
Research Grant