Biotherapeutics Chemistry, Pfizer Inc, 200 Cambridgepark Drive, Cambridge, MA 02140, USA.
Future Med Chem. 2014 Apr;6(6):675-95. doi: 10.4155/fmc.14.24.
Bruton's TK (BTK) is a promising biological target for therapeutic intervention of several diseases including inflammatory diseases and cancer/B cell malignancies. Numerous research groups are actively engaged in investigating the functions of BTK, and discovering potent and selective BTK inhibitors as drug candidates. Revealed by x-ray crystal structures with ligands of diverse chemical structures, the ability of BTK kinase domain to adopt various inactive conformations offers unique opportunities to identify highly potent and exquisitely selective inhibitors. Both reversible and covalent inhibitor approaches have yielded candidates demonstrating safety profiles and efficacies in multiple preclinical models of autoimmunity and oncology. Two BTK inhibitors have entered human clinical trials for oncology indications. Ibrutinib won the US FDA approval in November 2013 to become the first-in-class BTK inhibitor for treating mantle cell lymphoma. This encouraging outcome and the other on-going human studies could ultimately expand the utility of BTK inhibitors to broader autoimmune disease areas.
布鲁顿酪氨酸激酶（BTK）是一种有前途的生物靶点，可用于治疗多种疾病，包括炎症性疾病和 B 细胞恶性肿瘤。许多研究小组正在积极研究 BTK 的功能，并发现有效的、选择性的 BTK 抑制剂作为候选药物。通过与具有不同化学结构的配体的 X 射线晶体结构揭示，BTK 激酶结构域采用各种非活性构象的能力为鉴定高效和高选择性抑制剂提供了独特的机会。可逆和共价抑制剂方法都产生了候选药物，这些药物在自身免疫和肿瘤学的多种临床前模型中表现出安全性和疗效。两种 BTK 抑制剂已进入肿瘤适应证的人体临床试验。依鲁替尼于 2013 年 11 月获得美国 FDA 批准，成为治疗套细胞淋巴瘤的首个 BTK 抑制剂。这一令人鼓舞的结果和其他正在进行的人体研究最终可能将 BTK 抑制剂的用途扩展到更广泛的自身免疫疾病领域。
