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.
项目总结
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)
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Ozgur Sahin其他文献
Ozgur Sahin的其他文献
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{{ 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
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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:
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