Mologni Luca, Tardy Sébastien, Zambon Alfonso, Orsato Alexandre, Bisson William H, Ceccon Monica, Viltadi Michela, D'Attoma Joseph, Pannilunghi Sara, Vece Vito, Bertho Jerome, Goekjian Peter, Scapozza Leonardo, Gambacorti-Passerini Carlo
Dept. of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy.
Galkem srl, Monza 20900, Italy.
ACS Omega. 2022 May 11;7(20):17083-17097. doi: 10.1021/acsomega.2c00507. eCollection 2022 May 24.
The anaplastic lymphoma kinase (ALK) is abnormally expressed and hyperactivated in a number of tumors and represents an ideal therapeutic target. Despite excellent clinical responses to ALK inhibition, drug resistance still represents an issue and novel compounds that overcome drug-resistant mutants are needed. We designed, synthesized, and evaluated a large series of azacarbazole inhibitors. Several lead compounds endowed with submicromolar potency were identified. Compound showed selective inhibition of native and mutant drug-refractory ALK kinase as well as in a Ba/F3 model and in human ALK+ lymphoma cells. The three-dimensional (3D) structure of a :ALK-KD cocrystal is reported, showing extensive interaction through the hinge region and the catalytic lysine 1150.
间变性淋巴瘤激酶（ALK）在多种肿瘤中异常表达并过度激活，是一个理想的治疗靶点。尽管ALK抑制在临床上取得了良好疗效，但耐药性仍是一个问题，因此需要能够克服耐药突变体的新型化合物。我们设计、合成并评估了一系列氮杂咔唑抑制剂。鉴定出了几种具有亚微摩尔效力的先导化合物。化合物在Ba/F3模型和人ALK+淋巴瘤细胞中对天然和突变型耐药ALK激酶均表现出选择性抑制作用。报道了一种：ALK-KD共晶体的三维（3D）结构，显示通过铰链区和催化赖氨酸1150存在广泛相互作用。
