S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth.
S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth.
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DOI：
10.18632/oncotarget.24744
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发表时间：
2018-04-13
期刊：
影响因子：
--
通讯作者：
Geneste O
中科院分区：
文献类型：
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作者：
Casara P;Davidson J;Claperon A;Le Toumelin-Braizat G;Vogler M;Bruno A;Chanrion M;Lysiak-Auvity G;Le Diguarher T;Starck JB;Chen I;Whitehead N;Graham C;Matassova N;Dokurno P;Pedder C;Wang Y;Qiu S;Girard AM;Schneider E;Gravé F;Studeny A;Guasconi G;Rocchetti F;Maïga S;Henlin JM;Colland F;Kraus-Berthier L;Le Gouill S;Dyer MJS;Hubbard R;Wood M;Amiot M;Cohen GM;Hickman JA;Morris E;Murray J;Geneste O
逃避凋亡是癌细胞的主要标志之一。B细胞淋巴瘤2（BCL-2）基因家族编码促凋亡和抗凋亡蛋白，这些蛋白是凋亡过程的关键调节因子。促生存成员BCL-2的过表达是促成包括淋巴瘤和白血病在内的几种癌症的肿瘤发生和化学抗性的公认机制。因此，BCL-2已成为癌症治疗策略的有吸引力的靶标，如最近批准ABT-199（Venclexta™）用于具有17 p缺失的复发性或难治性慢性淋巴细胞白血病所证明的。在这里，我们描述了一种新的口服生物可利用的BCL-2选择性和有效的抑制剂，称为S55746（也称为BCL 201）。S55746占据BCL-2的疏水沟。其选择性特征表明与MCL-1、BFL-1（BCL 2A 1/A1）没有显著结合，并且对BCL-XL的亲和力差。因此，S55746对BCL-XL依赖性细胞如血小板没有细胞毒活性。在一组血液细胞系中，S55746诱导细胞凋亡的标志，包括磷脂酰丝氨酸的外化、半胱天冬酶-3活化和PARP裂解。在原发性慢性淋巴细胞白血病和套细胞淋巴瘤患者样本中，S55746在低纳摩尔范围内诱导细胞凋亡。最后，小鼠每日经口给予S55746在两种血液学异种移植模型中显示出稳健的抗肿瘤疗效，未出现体重减轻和行为变化。综上所述，这些数据表明，S55746是一种新型的，耐受性良好的BH 3模拟物，选择性和有效地靶向BCL-2蛋白。
Escape from apoptosis is one of the major hallmarks of cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, BCL-2 has become an attractive target for therapeutic strategy in cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion. Here, we describe a novel orally bioavailable BCL-2 selective and potent inhibitor called S55746 (also known as BCL201). S55746 occupies the hydrophobic groove of BCL-2. Its selectivity profile demonstrates no significant binding to MCL-1, BFL-1 (BCL2A1/A1) and poor affinity for BCL-XL. Accordingly, S55746 has no cytotoxic activity on BCL-XL-dependent cells, such as platelets. In a panel of hematological cell lines, S55746 induces hallmarks of apoptosis including externalization of phosphatidylserine, caspase-3 activation and PARP cleavage. Ex vivo, S55746 induces apoptosis in the low nanomolar range in primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma patient samples. Finally, S55746 administered by oral route daily in mice demonstrated robust anti-tumor efficacy in two hematological xenograft models with no weight lost and no change in behavior. Taken together, these data demonstrate that S55746 is a novel, well-tolerated BH3-mimetic targeting selectively and potently the BCL-2 protein.