一种靶向急性粒细胞白血病细胞的新型GATA2抑制剂的配体发现

J. Menendez-Gonzalez, K. Strange, Marcella Bassetto, A. Brancale, N. Rodrigues, S. Ferla
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摘要

尽管其他血液系统恶性肿瘤的治疗取得了重大进展,改善了患者的预后,但开发新的治疗方法来改善急性髓细胞白血病(AML)患者的预后仍然是一个未满足临床需求的领域。锌指转录因子GATA家族成员GATA2的过度表达与AML有关。在人类AML细胞中GATA2过表达的环境中,K7174,一种抑制GATA2的蛋白酶体抑制剂,在体外诱导细胞凋亡并增强AML化疗药物的杀伤活性,但靶向蛋白酶体,在临床上与高毒性有关。使用计算机方法,我们开始筛选特异性GATA2抑制剂,该抑制剂将独立于蛋白酶体靶向AML细胞。使用K7174的低能构象对内部小分子文库进行基于形状的虚拟筛选。随后根据其对GATA2相对于蛋白酶体的潜在选择性过滤虚拟命中化合物。从15种在体外评估其杀死AML细胞能力的选定化合物中,一种化合物,一种具有丙型肝炎抗病毒活性的不对称取代哌嗪,在没有蛋白酶体抑制的情况下,在AML细胞中表现出诱导细胞凋亡和减少细胞周期的优异能力。该化合物还能够促进复发繁殖的白血病干细胞(LSC)区室的细胞死亡,同时保留Gata2敲除的LSC,关键地证明了抑制Gata2的特异性。我们已经确定了一种GATA2特异性抑制剂,它具有在体外靶向AML细胞的良好能力,包括支持AML不良预后的LSCs。
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Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells
Despite major therapeutic advances leading to improved patient outcomes for other haematological malignancies, development of new therapeutics to improve prognosis for acute myeloid leukemia (AML) patients remains an area of unmet clinical need. Overexpression of GATA2, a member of the GATA family of zinc finger transcription factors, has been implicated in AML. In settings where GATA2 is overexpressed in human AML cells, K7174, a proteasome inhibitor that inhibits GATA2, induces apoptosis and enhances the killing activity of AML chemotherapeutics in vitro yet targeting the proteasome has been associated with high toxicity in the clinic. Using an in silico approach, we embarked on a screen to identify specific GATA2 inhibitors that will target AML cells independently of the proteasome. A shape-based virtual screening of an in-house library of small molecules was performed using a low-energy conformation of K7174. The virtual hit compounds were subsequently filtered according to their potential selectivity for GATA2 over the proteasome. From 15 selected compounds evaluated for their ability to kill AML cells in vitro, one compound, an asymmetrical substituted piperazine with Hepatitis C antiviral activity, exhibited superior ability to induce apoptosis and reduce cell cycling in AML cells without proteasome inhibition. This compound was also able to promote cell death of the relapse propagating leukemic stem cell (LSC) compartment while sparing Gata2 knockout LSCs, crucially demonstrating specificity to inhibit GATA2. We have identified a GATA2 specific inhibitor with promising capability to target AML cells in vitro, including LSCs that underpin poor prognosis in AML.
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