Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Cancer Cell. 2011 Apr 12;19(4):556-68. doi: 10.1016/j.ccr.2011.03.003.
Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead "switch-control" inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph(+) leukemia.
通过 ABL1 激酶结构域突变获得对 ABL1 酪氨酸激酶抑制剂（TKI）的耐药性，特别是关键突变 T315I，是慢性髓细胞白血病（CML）患者的一个重大问题。我们使用基于结构的药物设计开发了与 ABL1 用于在非活性和活性构象之间切换的残基（Arg386/Glu282）结合的化合物。先导“开关控制”抑制剂 DCC-2036 通过诱导 II 型非活性构象强烈抑制未磷酸化和磷酸化的 ABL1，并保留对大多数临床相关 CML 耐药突变体的疗效，包括 T315I。DCC-2036 抑制 BCR-ABL1(T315I)表达的细胞系，延长 T315I 突变 CML 和 B 淋巴细胞白血病小鼠模型中的存活时间，并抑制体外和体内表达 T315I 的原发性患者白血病细胞，支持其在 TKI 耐药性 Ph(+)白血病中的临床开发。
