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：
10166809
负责人：
Jin Wang
金额：
$ 64.16万
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/10166809
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/antagonist 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）是临床证明的衰减B细胞受体（BCR）信号的靶标 B细胞恶性肿瘤，包括地幔细胞淋巴瘤（MCL）和慢性淋巴细胞性白血病（CLL）。 ibrutinib， FDA批准了一等，每天一次的口服共价btk抑制剂，以治疗继电器/难治性MCL 2013年，基于由Michael Wang博士领导的多中心II期临床试验（该应用程序多PI）。尽管ibrutinib已成功治疗MCL和CLL，但获得的抵抗很快就会出现，主要是通过BTK激酶结构域中的突变，可以显着降低CLL中的Ibrutinib效率和激活 MCL中的替代生存途径。另外，使用激酶抑制剂破坏BTK的激酶功能是目前在此验证的目标上唯一可用的热干预。但是，BTK也可以增强抗原受体诱导的钙以激酶非依赖性方式，而激酶无活性BTK突变体可以部分挽救小鼠BTK-NULL B细胞的B细胞发育。在这个项目中，我们将开发一个小的分子治疗剂可以有效地抑制和降解细胞中的BTK，而与BTK突变无关完全废除BTK激酶和非激酶活性的状态。在我们的初步研究中，我们发展了 RC-1是第一个可逆共价基于化学的BTK降解器。基于我们高度有希望的初步研究，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，我们假设 RC-1的进一步优化将导致针对MCL，CLL和其他B细胞的下一代目标治疗恶性肿瘤并显着改善治疗结果。为了实现这一目标，我们组装了一个高度的具有完整专业知识的动机团队。 J. Wang博士是化学生物学和药物发现专家。他以前的工作导致开发了类固醇受体共激活剂的第一类抑制剂，这是在商业化下。他的实验室已经建立了完整的药物发现管道，包括有机合成，体外测定，ADMET分析和临床前效率测试。 M. Wang博士（MD Anderson）和博士 Woyach（俄亥俄州立大学）是淋巴瘤研究领域的主要科学家，专门研究BTK信号传导路径。 M Wang博士的临床研究导致了FDA批准了两种BTK抑制剂Ibrutinib和Acalabrutinib。 Woyach博士是抗ibrutinib耐药机制的领导者。在这个项目中，我们将进一步优化BTK降级器具有类似药物的特性，并测试MCL和CLL小鼠模型中的治疗效率。在我们和他人研究，在某些B细胞恶性肿瘤中，BTK降解器可能比抑制剂更有潜力。这个新颖的机制 BTK靶向的行动从未在诊所中探讨。我们希望成功完成项目将对B细胞Malignancys的治疗产生重大影响。