AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies
AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies
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DOI：
10.1158/2159-8290.cd-18-0387
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发表时间：
2018-12-01
期刊：
影响因子：
28.2
通讯作者：
Hughes, Paul E.
中科院分区：
文献类型：
--
作者：
Caenepeel, Sean;Brown, Sean P.;Hughes, Paul E.
促生存BCL 2家族成员MCL 1在癌症中经常失调。为了克服与抑制MCL 1蛋白质-蛋白质相互作用相关的重大挑战，我们严格应用了小分子构象限制，最终发现了AMG 176，这是第一个在人体中研究的选择性MCL 1抑制剂。我们证明，MCL 1抑制诱导血液癌细胞系，肿瘤异种移植模型，和主要患者样本的亚组细胞凋亡的快速和坚定的步骤。通过使用人MCL 1基因敲入小鼠，我们证明了AMG 176活性剂量下的MCL 1抑制是耐受的，并与明确的药效学效应相关，表现为B细胞、单核细胞和中性粒细胞减少。此外，AMG 176和维奈托克联合给药在急性髓性白血病（AML）肿瘤模型和耐受剂量的原发性患者样本中具有协同作用。这些结果突出了AMG 176的治疗前景和与其他BH 3 mimetics.Significance组合的潜力：AMG 176是一种有效的，选择性的，口服生物可利用的MCL 1抑制剂，诱导血液恶性肿瘤模型中的细胞凋亡的快速承诺。AMG 176和维奈托克的协同组合在AML模型中以耐受剂量显示出稳健的活性，突出了BH 3模拟物组合在血液学癌症中的前景。(C)2018年AACR。
The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein-protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the first selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics.SIGNIFICANCE: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers. (C) 2018 AACR.