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：
10442373
负责人：
Jin Wang
金额：
$ 62.87万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
https://reporter.nih.gov/project-details/10442373
关键词：
Acrylamides Active Sites Address Agammaglobulinaemia tyrosine kinase Antigen Receptors Attenuated B lymphoid malignancy B-Cell Antigen Receptor B-Cell Development B-Lymphocytes Binding Biology Boronic Acids Calcium Cell Line Cells Chemical Structure Chemicals Chemistry Chronic Lymphocytic Leukemia Clinic Clinical Clinical Research Complex Cysteine Development Drug resistance FDA approved Goals Half-Life In Vitro Industry Laboratories Lymphoma Lymphoma cell MDM2 gene Mantle Cell Lymphoma Methods Modeling Mus Mutation Natural regeneration Ohio Oral Organic Synthesis Pathway interactions Patients Permeability Pharmaceutical Preparations Phase II Clinical Trials Phosphotransferases Physicians Plasma Property Proteins Receptor Signaling Refractory Relapse Reporting Research Resistance Scientist Side Signal Pathway Steroid Receptors Sulfhydryl Compounds Therapeutic Agents Therapeutic Intervention Transgenic Organisms Treatment Efficacy Treatment outcome Tyrosine Kinase Inhibitor Work base chronic lymphocytic leukemia cell commercialization covalent bond design drug development drug discovery efficacy evaluation efficacy testing improved in vitro Assay in vitro activity in vivo inhibitor kinase inhibitor molecular dynamics molecular transporter mouse model mutant mutational status new therapeutic target next generation novel novel strategies nuclear receptor coactivator 1 patient derived xenograft model preclinical efficacy recruit resistance mechanism small molecule therapeutics targeted treatment therapeutic evaluation uptake

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.

抽象的 Bruton 的酪氨酸激酶 (BTK) 是一种经临床证明可减弱 B 细胞受体 (BCR) 信号传导的靶标 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)。首创、每日一次、口服共价 BTK 抑制剂经 FDA 批准用于治疗复发/难治性 MCL 2013年基于Michael Wang博士领导的多中心II期临床试验（本申请的多PI）。尽管依鲁替尼已成功治疗 MCL 和 CLL，但获得性耐药很快就会出现，主要是通过 BTK 激酶结构域的突变显着降低依鲁替尼对 CLL 的疗效以及激活此外，使用激酶抑制剂破坏 BTK 的激酶功能是 MCL 的替代生存途径。目前，BTK 是针对这一经过充分验证的靶标的唯一可用的治疗干预措施。抗原受体以不依赖于激酶的方式诱导钙流入，而激酶失活的 BTK 突变体可以部分挽救小鼠体内 BTK 缺失的 B 细胞的发育。在这个项目中，我们将开发一种小型的 B 细胞。无论BTK突变如何，都能有效抑制和降解细胞内的BTK的分子治疗剂在我们的初步研究中，我们开发了完全消除 BTK 激酶和非激酶活性的状态。 RC-1 是第一个基于可逆共价化学的 BTK 降解剂，基于我们非常有前途的初步结果。研究、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，我们捕捉到了这一点 RC-1的进一步优化将带来针对MCL、CLL和其他B细胞的下一代靶向治疗为了实现这一目标，我们组建了一个高度重视的团队。 J. Wang 博士是化学生物学和药物发现方面的专家。他之前的工作导致了类固醇受体共激活剂的一流抑制剂的开发，该抑制剂是他的实验室已经建立了完整的药物发现渠道，包括有机药物。合成、体外测定、ADMET 分析和临床前功效测试。 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 M Wang 博士的临床研究导致 FDA 批准了两种 BTK 抑制剂 ibrutinib 和 acalabrutinib。 Woyach 博士是 ibrutinib 耐药机制的领导者，在这个项目中，我们将进一步优化 BTK 降解剂。具有类似药物的特性，并在我们和其他人的 MCL 和 CLL 小鼠模型中测试治疗效果。研究表明，在某些 B 细胞恶性肿瘤中，BTK 降解剂比抑制剂更有效。 BTK 靶向的行动从未在临床中探索过，我们期望成功完成这一任务。该项目将对 B 细胞恶性肿瘤的治疗产生重大影响。