Reversible Covalent BTK Degraders as the Next Generation Targeted Therapy to Treat B-cell Malignancies

摘要 Bruton‘s酪氨酸激酶(BTK)是临床证实的抑制B细胞受体(BCR)信号转导的靶点。 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)。伊布鲁替尼，一种 FDA批准一种一流的、每日一次的口服共价BTK抑制剂用于治疗复发/难治性MCL 2013年，基于Michael Wang博士领导的多中心II期临床试验(此应用程序上的多PI)。 虽然伊布鲁替尼在治疗MCL和CLL方面取得了成功，但获得性耐药出现得很快，主要是 通过BTK激酶结构域的突变显著降低伊布鲁替尼对CLL的疗效和激活 MCL的不同生存途径。此外，使用激酶抑制剂干扰BTK的激酶功能是 这是目前对这一有效靶点的唯一可用的治疗干预。然而，BTK还可以增强 抗原受体以非依赖性方式诱导钙内流，而激酶失活的BTK突变体 能部分挽救小鼠BTK缺失型B细胞发育。在这个项目中，我们将开发一种小型 一种可有效抑制和降解细胞内BTK的分子治疗剂，与BTK突变无关 地位，以完全取消BTK激酶和非激酶活性。在我们的初步研究中，我们开发了 RC-1作为第一个可逆的基于共价化学的BTK降解剂。基于我们非常有希望的初步调查 研究，药物开发的广泛专业知识，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细胞的下一代靶向治疗 并显著改善治疗结果。为了实现这一目标，我们已经召集了一个高度 具有互补性专业知识的积极团队。J·王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辅助激活物一流抑制剂的开发，这是 正在商业化中。他的实验室已经建立了药物发现的完整流水线，包括有机药物 合成、体外试验、admet图谱和临床前疗效试验。M·王博士(MD Anderson)和Dr. 沃亚克(俄亥俄州立大学)是淋巴瘤研究的领先内科科学家，专门研究BTK信号 路径。M Wang博士的临床研究导致FDA批准了两种BTK抑制剂，ibrutinib和acalabrutinib。 沃亚奇博士是伊布鲁替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 具有类药物特性，并在MCL和CLL小鼠模型上测试治疗效果。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。这一新机制 BTK靶向的作用机制在临床上从未被探索过。我们期待着这一工作的圆满完成 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.