Inhibition of Bcl-xL by Targeted Degradation
通过靶向降解抑制 Bcl-xL
基本信息
- 批准号:10378075
- 负责人:
- 金额:$ 49.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAcute Myelocytic LeukemiaAcute T Cell LeukemiaAdverse effectsAntineoplastic AgentsApoptosisApoptoticBCL2 geneBCL2L1 geneBiological AssayBlood PlateletsCancer RelapseCellsChemoresistanceChemotherapy and/or radiationChronic Lymphocytic LeukemiaClinicClinical TrialsCoupledCytometryDataDependenceDevelopmentDexamethasoneDose-LimitingDoxorubicinDrug KineticsDrug resistanceEvaluationExhibitsFormulationGoalsHumanIn VitroLeadLeukemia Acute Lymphoblastic ChemotherapyLigandsMCL1 geneMalignant NeoplasmsMediatingMusNamesNeoplasm MetastasisPatientsPharmaceutical PreparationsPhenotypePlayPositioning AttributePropertyProtacProtein FamilyProteinsRefractoryRelapseResearchResistanceRoleSeriesSpecificityT-LymphocyteTechniquesTechnologyTestingTherapeuticThrombocytopeniaTissuesToxic effectTreatment EfficacyVincristineWateranaloganti-cancerasparaginasebasebcl-xlong proteincancer cellcancer therapycancer typechemotherapyclinical applicationclinically relevantdesigndrug discoveryefficacy evaluationimprovedin vitro Assayin vivoin vivo evaluationinhibitorinnovationleukemiamouse modelnovelnovel strategiespatient derived xenograft modelpreclinical efficacypreventprotein degradationrecruitscale upsenescencesmall moleculestandard of caresuccesstargeted cancer therapytargeted treatmenttumor initiationtumor xenograftubiquitin-protein ligase
项目摘要
Targeting the anti-apoptotic Bcl-2 family proteins is a promising therapeutic strategy for cancer and has been
validated by the FDA approval of the Bcl-2 selective inhibitor, venetoclax, for the treatment of chronic lymphocytic
leukemia (CLL) and acute myeloid leukemia (AML). Given the well-documented importance of Bcl-xL to many
types of cancers, including most T-cell acute lymphoblastic leukemia (T-ALL), and its contribution to drug
resistance, Bcl-xL has become one of the best validated cancer targets. Unfortunately, the on-target and dose-
limiting platelet toxicity associated with the inhibition of Bcl-xL has prevented the use of Bcl-xL inhibitors in the
clinic. To circumvent this toxicity, we have applied the Proteolysis Targeting Chimera (PROTAC) technology to
design small-molecules that target Bcl-xL to E3 ligases for degradation. Our hypothesis is that Bcl-xL degrading
PROTACs (named as Bcl-Ps) designed to recruit an E3 ligase that is minimally expressed in platelets for the
targeted degradation of Bcl-xL will have reduced platelet toxicity and improved antitumor activity compared with
their corresponding Bcl-xL inhibitors. This hypothesis is supported by our strong preliminary results, including in
vivo efficacy data in T-ALL patient-derived xenograft (PDX) mouse models and other tumor xenograft mouse
models. In addition, our Bcl-Ps are also potent senolytic agents that can selectively kill senescent cells (SnCs),
because SnCs also rely on Bcl-xL for survival. Clearance of chemotherapy-induced SnCs is considered as a
novel strategy to prevent or reduce many short- and long-term adverse effects of the chemotherapeutic drugs,
as well as cancer relapse and metastasis. Collectively, these findings suggest that Bcl-Ps are superior to
conventional Bcl-xL inhibitors as anticancer agents. The goal of this application is to: (1) optimize Bcl-Ps for
improved potency, selectivity, drug-like properties, and in vivo efficacy; (2) evaluate the new Bcl-Ps through a
series of in vitro and in vivo assays; and (3) evaluate the preclinical efficacy of lead Bcl-Ps in T-ALL PDX models.
Upon completion of this project, we aim to produce Bcl-Ps amenable to further evaluation in clinical trials for T-
ALL, an aggressive leukemia that currently has no targeted therapies.
靶向抗凋亡Bcl-2家族蛋白是一种很有前途的治疗癌症的策略,并已被证实
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 }}
Marina Y Konopleva其他文献
Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML
阿扎胞苷、维奈托克和 Gilteritinib 治疗新诊断和复发或难治性 FLT3 突变 AML
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:45.3
- 作者:
N. Short;N. Daver;C. Dinardo;T. Kadia;L. Nasr;W. Macaron;M. Yilmaz;G. Borthakur;G. Montalban;G. Garcia;G. Issa;K. Chien;E. Jabbour;Cedric Nasnas;Xuelin Huang;W. Qiao;J. Matthews;Christopher J Stojanik;K. Patel;R. Abramova;J. Thankachan;Marina Y Konopleva;H. Kantarjian;F. Ravandi - 通讯作者:
F. Ravandi
Marina Y Konopleva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('Marina Y Konopleva', 18)}}的其他基金
Defining the novel cancer testis antigen HSPA1L as immunotherapeutic target in AML
将新型癌症睾丸抗原 HSPA1L 定义为 AML 的免疫治疗靶点
- 批准号:
10625516 - 财政年份:2022
- 资助金额:
$ 49.56万 - 项目类别:
Defining the novel cancer testis antigen HSPA1L as immunotherapeutic target in AML
将新型癌症睾丸抗原 HSPA1L 定义为 AML 的免疫治疗靶点
- 批准号:
10433726 - 财政年份:2022
- 资助金额:
$ 49.56万 - 项目类别:
Inhibition of Bcl-xL by Targeted Degradation
通过靶向降解抑制 Bcl-xL
- 批准号:
10737840 - 财政年份:2020
- 资助金额:
$ 49.56万 - 项目类别:
Chaperone-Mediated Protein Degradation of Bcl-xL and Bcl-2
分子伴侣介导的 Bcl-xL 和 Bcl-2 蛋白质降解
- 批准号:
10599452 - 财政年份:2020
- 资助金额:
$ 49.56万 - 项目类别:
Inhibition of Bcl-xL by Targeted Degradation
通过靶向降解抑制 Bcl-xL
- 批准号:
10133018 - 财政年份:2020
- 资助金额:
$ 49.56万 - 项目类别:
Inhibition of Bcl-xL by Targeted Degradation
通过靶向降解抑制 Bcl-xL
- 批准号:
10644990 - 财政年份:2020
- 资助金额:
$ 49.56万 - 项目类别:
Targeting apoptosis in high-risk AML and MDS with BCL-2 inhibitor Venetoclax and optimized 10-day Decitabine regimen
使用 BCL-2 抑制剂 Venetoclax 和优化的 10 天地西他滨方案靶向高危 AML 和 MDS 中的细胞凋亡
- 批准号:
10415997 - 财政年份:2019
- 资助金额:
$ 49.56万 - 项目类别:
Targeting apoptosis in high-risk AML and MDS with BCL-2 inhibitor Venetoclax and optimized 10-day Decitabine regimen
使用 BCL-2 抑制剂 Venetoclax 和优化的 10 天地西他滨方案靶向高危 AML 和 MDS 中的细胞凋亡
- 批准号:
10654631 - 财政年份:2019
- 资助金额:
$ 49.56万 - 项目类别:
Targeting mitochondrial complex I in acute lymphoblastic leukemia
靶向急性淋巴细胞白血病中的线粒体复合物 I
- 批准号:
9815737 - 财政年份:2019
- 资助金额:
$ 49.56万 - 项目类别:
相似海外基金
Computing analysis of leukemic stem cell dynamics in acute myelocytic leukemia
急性粒细胞白血病白血病干细胞动力学的计算分析
- 批准号:
19K08356 - 财政年份:2019
- 资助金额:
$ 49.56万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Generation of immunotoxins with super-targeting mAb in the acute myelocytic leukemia
在急性髓细胞白血病中使用超靶向单克隆抗体产生免疫毒素
- 批准号:
23501309 - 财政年份:2011
- 资助金额:
$ 49.56万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
急性粒细胞白血病反应的决定因素
- 批准号:
3556971 - 财政年份:1980
- 资助金额:
$ 49.56万 - 项目类别:
DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
急性粒细胞白血病反应的决定因素
- 批准号:
3556968 - 财政年份:1980
- 资助金额:
$ 49.56万 - 项目类别:
ERADICATION OF ACUTE MYELOCYTIC LEUKEMIA CELLS BY MAB THERAPY
通过 MAB 疗法根除急性粒细胞白血病细胞
- 批准号:
3889304 - 财政年份:
- 资助金额:
$ 49.56万 - 项目类别: