Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK).
Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK).
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DOI：
10.1016/j.ejmech.2018.03.071
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发表时间：
2018-05-10
影响因子：
6.7
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Zhang C;Han XR;Yang X;Jiang B;Liu J;Xiong Y;Jin J
间变性淋巴瘤激酶（ALK）激活与许多类型的人类癌症相关。已经投入了大量的努力来开发ALK抑制剂以拮抗ALK的激酶活性。迄今为止，四种ALK抑制剂已被FDA批准用于治疗ALK阳性非小细胞肺癌（NSCLC）患者。然而，在大多数接受这些抑制剂治疗的患者中观察到耐药性。新的治疗策略（例如，具有新作用机制的化合物）来克服耐药性问题。新兴的PROTAC（Proteolysis Targeting Chimera）技术已成功应用于选择性降解多种蛋白质靶标，但不包括ALK。由于ALK蛋白水平对哺乳动物的生存能力并不重要，因此ALK PROTAC可能导致毒性最小的新型治疗方法。在这里，我们报告了ALK的新型PROTAC（降解剂）的设计、合成和生物学评价。MS 4077（5）和MS 4078（6）以浓度和时间依赖性方式有效降低SU-DHL-1淋巴瘤和NCI-H2228肺癌细胞中致癌活性ALK融合蛋白的细胞水平。化合物5和6诱导的ALK蛋白降解是cereblon和蛋白酶体依赖性的。此外，化合物5和6有效地抑制SU-DHL-1细胞的增殖。此外，化合物6在小鼠药代动力学研究中显示出良好的血浆暴露，因此适合于体内功效研究。我们还开发了MS 4748（7）和MS 4740（8），分别是5和6的非常接近的类似物，它们不能降解ALK融合蛋白，作为阴性对照。化合物5 - 8是用于研究ALK药理学降解作用的有价值的化学工具。我们的研究为开发下一代ALK PROTAC铺平了道路。
Anaplastic lymphoma kinase (ALK) activation has been associated with many types of human cancer. Significant efforts have been devoted to development of ALK inhibitors to antagonize the kinase activity of ALK. Four ALK inhibitors have been approved by the FDA to date for treating patients with ALK-positive non-small cell lung cancers (NSCLC). However, drug resistance has been observed in the majority of patients treated with these inhibitors. New therapeutic strategies (e.g., compounds with novel mechanisms of action) are needed to overcome the drug resistance issue. The emerging PROTAC (Proteolysis Targeting Chimera) technology has been successfully applied to selective degradation of multiple protein targets, but not ALK. Since ALK protein levels are not important for viability in mammals, ALK PROTACs could lead to novel therapeutics with minimal toxicity. Here we report the design, synthesis and biological evaluation of novel PROTACs (degraders) of ALK. MS4077 (5) and MS4078 (6) potently decreased cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by compounds 5 and 6 was cereblon and proteasome dependent. In addition, compounds 5 and 6 potently inhibited proliferation of SU-DHL-1 cells. Furthermore, compound 6 displayed good plasma exposure in a mouse pharmacokinetic study, thus is suitable for in vivo efficacy studies. We also developed MS4748 (7) and MS4740 (8), very close analogs of 5 and 6 respectively, which are incapable to degrade the ALK fusion proteins, as negative controls. Compounds 5 – 8 are valuable chemical tools for investigating effects of ALK pharmacological degradation. Our study paved the way for developing the next generation of ALK PROTACs.
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影响因子：
28.2
作者：
Friboulet L;Li N;Katayama R;Lee CC;Gainor JF;Crystal AS;Michellys PY;Awad MM;Yanagitani N;Kim S;Pferdekamper AC;Li J;Kasibhatla S;Sun F;Sun X;Hua S;McNamara P;Mahmood S;Lockerman EL;Fujita N;Nishio M;Harris JL;Shaw AT;Engelman JA
通讯作者：
Engelman JA
DOI：
10.1073/pnas.1321937111
发表时间：
2014-03-18
影响因子：
11.1
作者：
Kelly, Lindsey M.;Barila, Guillermo;Nikiforov, Yuri E.
通讯作者：
Nikiforov, Yuri E.
影响因子：
14.8
作者：
Bondeson DP;Mares A;Smith IE;Ko E;Campos S;Miah AH;Mulholland KE;Routly N;Buckley DL;Gustafson JL;Zinn N;Grandi P;Shimamura S;Bergamini G;Faelth-Savitski M;Bantscheff M;Cox C;Gordon DA;Willard RR;Flanagan JJ;Casillas LN;Votta BJ;den Besten W;Famm K;Kruidenier L;Carter PS;Harling JD;Churcher I;Crews CM
通讯作者：
Crews CM
影响因子：
1.8
作者：
Holla VR;Elamin YY;Bailey AM;Johnson AM;Litzenburger BC;Khotskaya YB;Sanchez NS;Zeng J;Shufean MA;Shaw KR;Mendelsohn J;Mills GB;Meric-Bernstam F;Simon GR
通讯作者：
Simon GR
影响因子：
8
作者：
Iwahara, T;Fujimoto, J;Yamamoto, T
通讯作者：
Yamamoto, T