Martins Diego M, Fernandes Philipe O, Vieira Lucas A, Maltarollo Vinícius G, Moraes Adolfo H
Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, 31270-901, Pampulha, MG, Brazil.
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, 31270-901, Pampulha, MG, Brazil.
Chembiochem. 2024 Dec 2;25(23):e202400296. doi: 10.1002/cbic.202400296. Epub 2024 Sep 12.
The human protein Abelson kinase (Abl), a tyrosine kinase, plays a pivotal role in developing chronic myeloid leukemia (CML). Abl's involvement in various signaling pathways underscores its significance in regulating fundamental biological processes, including DNA damage responses, actin polymerization, and chromatin structural changes. The discovery of the Bcr-Abl oncoprotein, resulting from a chromosomal translocation in CML patients, revolutionized the understanding and treatment of the disease. The introduction of targeted therapies, starting with interferon-alpha and culminating in the development of tyrosine kinase inhibitors (TKIs) like imatinib, significantly improved patient outcomes. However, challenges such as drug resistance and side effects persist, indicating the necessity of research into novel therapeutic strategies. This review describes advancements in Abl kinase inhibitor development, emphasizing rational compound design from structural and regulatory information. Strategies, including bivalent inhibitors, PROTACs, and compounds targeting regulatory domains, promise to overcome resistance and minimize side effects. Additionally, leveraging the intricate structure and interactions of Bcr-Abl may provide insights into developing inhibitors for other kinases. Overall, this review highlights the importance of continued research into Abl kinase inhibition and its broader implications for therapeutic interventions targeting kinase-driven diseases. It provides valuable insights and strategies that may guide the development of next-generation therapies.
人类蛋白阿贝尔森激酶（Abl）是一种酪氨酸激酶，在慢性髓系白血病（CML）的发生发展中起关键作用。Abl参与多种信号通路，这突出了其在调节包括DNA损伤反应、肌动蛋白聚合和染色质结构变化等基本生物学过程中的重要性。CML患者染色体易位产生的Bcr-Abl癌蛋白的发现，彻底改变了对该疾病的认识和治疗方法。从α干扰素开始，到伊马替尼等酪氨酸激酶抑制剂（TKIs）的开发，靶向治疗的引入显著改善了患者的治疗效果。然而，耐药性和副作用等挑战依然存在，这表明研究新的治疗策略很有必要。本综述描述了Abl激酶抑制剂开发的进展，强调从结构和调控信息进行合理的化合物设计。包括双价抑制剂、PROTACs以及靶向调控结构域的化合物等策略，有望克服耐药性并将副作用降至最低。此外，利用Bcr-Abl的复杂结构和相互作用，可能为开发其他激酶的抑制剂提供思路。总体而言，本综述强调了持续研究Abl激酶抑制及其对激酶驱动疾病治疗干预的更广泛意义的重要性。它提供了有价值的见解和策略，可能指导下一代疗法的开发。
