Reversible Covalent BTK Degraders as the Next Generation Targeted Therapy to Treat B-cell Malignancies
可逆共价 BTK 降解剂作为治疗 B 细胞恶性肿瘤的下一代靶向疗法
基本信息
- 批准号:10737768
- 负责人:
- 金额:$ 7.08万
- 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:2020-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcrylamidesActive SitesAgammaglobulinaemia tyrosine kinaseAntigen ReceptorsAttenuatedB lymphoid malignancyB-Cell Antigen ReceptorB-Cell DevelopmentB-LymphocytesBindingBiologyBoronic AcidsCalciumCell LineCellsChemical StructureChemicalsChemistryChronic Lymphocytic LeukemiaClinicClinicalClinical ResearchComplexCysteineDevelopmentDrug resistanceFDA approvedGoalsHalf-LifeIn VitroIndustryLaboratoriesLymphomaLymphoma cellMDM2 geneMantle Cell LymphomaMethodsModelingMusMutationNatural regenerationOhioOralOrganic SynthesisPathway interactionsPatientsPermeabilityPharmaceutical PreparationsPhase II Clinical TrialsPhosphotransferasesPhysiciansPlasmaPropertyProteinsReactionReceptor SignalingRefractoryRelapseReportingResearchResistanceScientistSideSignal PathwaySteroid ReceptorsSulfhydryl CompoundsTherapeutic AgentsTherapeutic InterventionTransgenic OrganismsTreatment EfficacyTreatment outcomeTyrosine Kinase InhibitorWorkchronic lymphocytic leukemia cellcommercializationcovalent bonddesigndrug developmentdrug discoveryefficacy evaluationefficacy testingimprovedin vitro Assayin vitro activityin vivoinhibitorkinase inhibitormolecular dynamicsmolecular transportermouse modelmutantmutational statusnew therapeutic targetnext generationnovelnovel strategiespatient derived xenograft modelpreclinical efficacyrecruitresistance mechanismsmall molecule therapeuticstargeted treatmenttherapeutic evaluationuptake
项目摘要
Abstract
Bruton’s Tyrosine Kinase (BTK) is a clinically proven target to attenuate B-cell receptor (BCR) signaling in
B-cell malignancies, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Ibrutinib, a
first-in-class, once-daily, oral covalent BTK inhibitor was approved by the FDA to treat relapsed/refractory MCL
in 2013 based on the multiple-center Phase II clinical trial led by Dr. Michael Wang (multi-PI on this application).
Although ibrutinib has been successful in treating MCL and CLL, acquired resistance arises quickly, mostly
through mutations in the BTK kinase domain to significantly reduce ibrutinib efficacy in CLL and the activation of
alternative survival pathways in MCL. Additionally, disrupting kinase function of BTK using kinase inhibitors is
the only currently available therapeutic intervention on this well-validated target. However, BTK can also enhance
antigen receptor-induced calcium influx in a kinase-independent manner, while a kinase inactive BTK mutant
can partially rescue B cell development of BTK-null B cells in mice. In this project, we will develop a small
molecule therapeutic agent that can efficiently inhibit and degrade BTK in cells irrespective of BTK mutation
status to abolish both BTK kinase and non-kinase activities completely. In our preliminary studies, we developed
RC-1 as the first reversible covalent chemistry-based BTK degrader. Based on our highly promising preliminary
studies, extensive expertise in drug development, and clinical expertise in MCL and CLL, we hypothesize that
further optimization of RC-1 will lead to a next-generation targeted therapy for MCL, CLL and other B-cell
malignances and significantly improve treatment outcomes. To achieve this goal, we have assembled a highly
motivated team with complementary expertise. Dr. J. Wang is an expert in chemical biology and drug discovery.
His previous work led to the development of the first-in-class inhibitor for steroid receptor coactivators, which is
under commercialization. His laboratory has established the full pipeline for drug discovery, including organic
synthesis, in vitro assays, ADMET profiling and preclinical efficacy testing. Dr. M. Wang (MD Anderson) and Dr.
Woyach (Ohio State) are leading physician scientists in lymphoma research, specializing in the BTK signaling
pathway. Dr. M Wang’s clinical studies led to the FDA approval of two BTK inhibitors, ibrutinib and acalabrutinib.
Dr. Woyach is a leader in ibrutinib-resistant mechanisms. In this project, we will further optimize BTK degraders
with drug-like properties and test the therapeutic efficacies in MCL and CLL mouse models. In our and others’
studies, BTK degraders can be more potent than inhibitors in certain B cell malignancies. This novel mechanism
of action for BTK targeting has never been explored in the clinic. We expect that successful completion of this
project will make a significant impact on the treatments of B-cell malignancies.
摘要
布鲁顿酪氨酸激酶(BTK)是临床上证实的减弱B细胞受体(BCR)信号传导的靶点,
B细胞恶性肿瘤,包括套细胞淋巴瘤(MCL)和慢性淋巴细胞白血病(CLL)。伊布替尼a
FDA批准了一种一流的每日一次口服共价BTK抑制剂,用于治疗复发性/难治性MCL
2013年,基于Michael Wang博士(本申请多名PI)领导的多中心II期临床试验。
尽管伊曲替尼已成功治疗MCL和CLL,但获得性耐药很快出现,大多数情况下,
通过BTK激酶结构域的突变,显著降低依鲁替尼在CLL中的疗效,
MCL中的替代生存途径。此外,使用激酶抑制剂破坏BTK的激酶功能是可行的。
这是目前唯一有效的针对这一目标的治疗干预。然而,BTK也可以增强
抗原受体以激酶非依赖性方式诱导钙内流,而激酶失活的BTK突变体
可以部分拯救小鼠中BTK缺失B细胞的B细胞发育。在这个项目中,我们将开发一个小型的
可有效抑制和降解细胞中的BTK而与BTK突变无关的分子治疗剂
完全消除BTK激酶和非激酶活性的状态。在我们的初步研究中,
RC-1是第一种基于可逆共价化学的BTK降解剂。根据我们非常有希望的初步调查
研究,在药物开发方面的广泛专业知识,以及MCL和CLL的临床专业知识,我们假设,
RC-1的进一步优化将导致下一代MCL,CLL和其他B细胞的靶向治疗
并显著改善治疗效果。为了实现这一目标,我们组织了一个高度
具有互补专业知识的积极团队。J. Wang博士是化学生物学和药物发现方面的专家。
他以前的工作导致了类固醇受体辅激活剂的第一种抑制剂的开发,
在商业化。他的实验室已经建立了完整的药物发现管道,包括有机药物。
合成、体外测定、ADMET谱分析和临床前功效测试。M博士Wang(MD安德森)和Dr.
Woyach(俄亥俄州)是淋巴瘤研究领域的领先医师科学家,专门研究BTK信号传导
通路M Wang博士的临床研究导致FDA批准了两种BTK抑制剂,伊曲替尼和acalabrutinib。
博士Woyach是伊匹尼耐药机制的领导者。在这个项目中,我们将进一步优化BTK降解器
并在MCL和CLL小鼠模型中测试治疗功效。在我们和其他人的
研究表明,在某些B细胞恶性肿瘤中,BTK降解剂可能比抑制剂更有效。这种新颖的机制
BTK靶向的作用机制从未在临床上探索过。我们期待这一工作的顺利完成,
该项目将对B细胞恶性肿瘤的治疗产生重大影响。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Steroid receptor coactivator-3 inhibition generates breast cancer antitumor immune microenvironment.
- DOI:10.1186/s13058-022-01568-2
- 发表时间:2022-10-31
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Applications of covalent chemistry in targeted protein degradation.
- DOI:10.1039/d2cs00362g
- 发表时间:2022-11-14
- 期刊:
- 影响因子:46.2
- 作者:Lu, Dong;Yu, Xin;Lin, Hanfeng;Cheng, Ran;Monroy, Erika Y.;Qi, Xiaoli;Wang, Meng C.;Wang, Jin
- 通讯作者:Wang, Jin
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Jin Wang其他文献
Jin Wang的其他文献
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{{ truncateString('Jin Wang', 18)}}的其他基金
Mathematical Modeling and Scientific Computing for Infectious Disease Research
传染病研究的数学建模和科学计算
- 批准号:
10793008 - 财政年份:2023
- 资助金额:
$ 7.08万 - 项目类别:
Development of First-in-Class RIPK1 Degraders to Improve Cancer Immunotherapies
开发一流的 RIPK1 降解剂以改善癌症免疫疗法
- 批准号:
10390589 - 财政年份:2022
- 资助金额:
$ 7.08万 - 项目类别:
Development of First-in-Class RIPK1 Degraders to Improve Cancer Immunotherapies
开发一流的 RIPK1 降解剂以改善癌症免疫疗法
- 批准号:
10661495 - 财政年份:2022
- 资助金额:
$ 7.08万 - 项目类别:
Development of First-in-Class RIPK1 Degraders to Improve Cancer Immunotherapies
开发一流的 RIPK1 降解剂以改善癌症免疫疗法
- 批准号:
10746264 - 财政年份:2022
- 资助金额:
$ 7.08万 - 项目类别:
Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的新型可溶性环氧化物水解酶抑制剂
- 批准号:
10503835 - 财政年份:2020
- 资助金额:
$ 7.08万 - 项目类别:
Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的新型可溶性环氧化物水解酶抑制剂
- 批准号:
10802956 - 财政年份:2020
- 资助金额:
$ 7.08万 - 项目类别:
Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的新型可溶性环氧化物水解酶抑制剂
- 批准号:
10412114 - 财政年份:2020
- 资助金额:
$ 7.08万 - 项目类别:
Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的新型可溶性环氧化物水解酶抑制剂
- 批准号:
10663178 - 财政年份:2020
- 资助金额:
$ 7.08万 - 项目类别:
Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的新型可溶性环氧化物水解酶抑制剂
- 批准号:
10261446 - 财政年份:2020
- 资助金额:
$ 7.08万 - 项目类别:
Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的新型可溶性环氧化物水解酶抑制剂
- 批准号:
10032662 - 财政年份:2020
- 资助金额:
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