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Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia
Science Translational Medicine ( IF 15.8 ) Pub Date : 2018-04-11 , DOI: 10.1126/scitranslmed.aao3003
Luis A. Carvajal 1 , Daniela Ben Neriah 1 , Adrien Senecal 2 , Lumie Benard 1 , Victor Thiruthuvanathan 1 , Tatyana Yatsenko 1 , Swathi-Rao Narayanagari 1, 3 , Justin C. Wheat 1 , Tihomira I. Todorova 1 , Kelly Mitchell 1 , Charles Kenworthy 2 , Vincent Guerlavais 4 , D. Allen Annis 4 , Boris Bartholdy 1 , Britta Will 1, 3, 5, 6 , Jesus D. Anampa 5 , Ioannis Mantzaris 5 , Manuel Aivado 4 , Robert H. Singer 2 , Robert A. Coleman 2 , Amit Verma 3, 5, 6 , Ulrich Steidl 1, 3, 5, 6
Affiliation  

The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. We demonstrate that dual MDMX/MDM2 inhibition with a stapled α-helical peptide (ALRN-6924), which has recently entered phase I clinical testing, produces marked antileukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single-cell and single-molecule levels and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in vivo. Dual MDMX/MDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells, including leukemic stem cell–enriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 markedly improves survival in AML xenograft models. Our study provides mechanistic insight to support further testing of ALRN-6924 as a therapeutic approach in AML and other cancers with wild-type p53.



中文翻译:

双重抑制MDMX和MDM2作为白血病的治疗策略

肿瘤抑制因子p53通常通过与内源性抑制剂小鼠双4分钟同系物(MDM4或MDMX)或小鼠双2分钟同系物(MDM2)的相互作用而失活,它们在急性髓细胞性白血病(AML)和其他癌症患者中经常过表达。长期以来,一直寻求将这两种相互作用的药理学破坏作为一种有吸引力的策略,以完全恢复具有野生型p53的癌症中p53依赖性肿瘤抑制因子的活性。迄今为止,该途径的选择性靶向仅限于对MDMX缺乏亲和力的仅MDM2的小分子抑制剂。我们证明,最近已进入I期临床试验的具有钉合α-螺旋肽(ALRN-6924)的双重MDMX / MDM2抑制作用产生了显着的抗白血病作用。ALRN-6924可在单细胞和单分子水平上强烈激活p53依赖性转录,并在体外和体内在白血病细胞中展现出生化和分子生物学的靶向活性。ALRN-6924对MDMX / MDM2的双重抑制作用通过诱导细胞系和原发性AML患者细胞(包括富集白血病干细胞的细胞)的细胞周期停滞和凋亡,从而抑制细胞增殖,并破坏功能性克隆发生和连续重铸的能力。此外,ALRN-6924显着提高了AML异种移植模型的存活率。我们的研究提供了机械方面的见识,以支持进一步检测ALRN-6924,将其作为AML和其他野生型p53癌症的治疗方法。ALRN-6924对MDMX / MDM2的双重抑制作用通过诱导细胞系和原发性AML患者细胞(包括富集白血病干细胞的细胞)的细胞周期停滞和凋亡,从而抑制细胞增殖,并破坏功能性克隆发生和连续重铸的能力。此外,ALRN-6924显着提高了AML异种移植模型的存活率。我们的研究提供了机械方面的见识,以支持进一步检测ALRN-6924,将其作为AML和其他野生型p53癌症的治疗方法。ALRN-6924对MDMX / MDM2的双重抑制作用通过诱导细胞系和原发性AML患者细胞(包括富集白血病干细胞的细胞)的细胞周期停滞和凋亡,从而抑制细胞增殖,并破坏功能性克隆发生和连续重铸的能力。此外,ALRN-6924显着提高了AML异种移植模型的存活率。我们的研究提供了机械方面的见识,以支持进一步检测ALRN-6924,将其作为AML和其他野生型p53癌症的治疗方法。

更新日期:2018-04-12
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