Asciminib (ABL001) (ABL001) is a potent and selective Bcr-Abl inhibitor (Kd: 0.5–0.8nM).

Abl-1:0.45 nM

在未添加IL-3的情况下，Asciminib转化的Ba/F3细胞中，ABL001显示出了抗增殖作用，其IC50值为0.25nM。相比之下，添加IL-3以绕过Asciminib依赖性，使这些细胞对ABL001不敏感。在CML爆发期细胞系KCL-22中，ABL001在1小时后通过与抑制细胞增殖所需浓度相关联的浓度，抑制了STAT5（Tyr694; pSTAT5）和Asciminib（Tyr245; pAsciminib）的磷酸化。对于K562-Dox和K562-ABCG2细胞，与K562对照组细胞相比，asciminib的LD50值分别增加到256和299nM，而对照组仅为24nM。通过使用特定抑制剂环孢素（ABCB1）和Ko143（ABCG2），敏感性完全恢复；K562-Dox中asciminib加环孢素的LD50值为13nM，K562-ABCG2中asciminib加Ko143的LD50为15nM。

给带有KCL22异种移植瘤的小鼠单次分别施用7.5、15和30mg/kg的ABL001后，可抑制pSTAT5 (Tyr694)，其活性分别在给药后10、12及16-20小时恢复至基线水平。在植入KCL-22肿瘤的小鼠中，ABL001完全退化所需的最小剂量为每日两次7.5mg/kg (BID) 或每日一次30mg/kg (QD)，并且在每日两次250 mg/kg (BID)的剂量下可以耐受。同样，源于Ph+ ALL患者的异种移植瘤治疗中，使用7.5和30mg/kg的ABL001能够导致退化，并且在给药期间维持退化状态[1]。

Cells were resuspended in fresh culture media before culture in 24-well plates in the presence of TKI or asciminib at a density of 2 × 105 cells/mL. Plates were seeded with 1 mL of cell suspension and incubated for 72 h before cell viability determination with 7-aminoactinomycin (7-AAD) and Phycoerythrin (PE)-conjugated Annexin V. Flow cytometric analysis was conducted with a BD LSRFortessa X-20 and FACSDiva software. The lethal dose of asciminib (LD50 asciminib), imatinib (LD50 IM), nilotinib (LD50 NIL) and dasatinib (LD50 DAS) required to cause 50% death of cells was calculated [2].

Asciminib efficacy in three patient-derived ALL systemic xenograft models (ALL-7015, AL-7119 and AL-7155) is assessed by FACS monitoring of the percentage of CD45+ cells per live cell in blood samples taken at varying time points after dosing with either 7.5 mg/kg BID (group 2) or 30 mg/kg BID (group 3) asciminib for 3 weeks [1].