Reversible Covalent BTK Degraders as the Next Generation Targeted Therapy to Treat 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。

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.