Pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of RET: Design, synthesis and biological evaluation.
Pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of RET: Design, synthesis and biological evaluation.
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吡罗洛[2,3-D]嘧啶衍生物作为RET的抑制剂：设计，合成和生物学评估。
DOI：
10.1016/j.ejmech.2020.112691
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发表时间：
2020-11-15
影响因子：
6.7
通讯作者：
Li, Hong-yu
中科院分区：
文献类型：
--
作者：
Lakkaniga, Naga Rajiv;Gunaganti, Naresh;Zhang, Lingtian;Belachew, Binyam;Frett, Brendan;Leung, Yuet-Kin;Li, Hong-yu
关键词：
RET激酶的基因融合和点突变对于驱动胸部癌症，包括甲状腺癌和非小细胞肺癌至关重要。已经合成了基于不同杂环的各种支架并将其评价为RET抑制剂。在这项工作中，我们研究了吡咯并[2，3-d]嘧啶衍生物用于抑制RET-wt、耐药突变体RET V804 M和RET基因融合驱动的细胞系。合成了几种化合物，并进行了广泛的构效关系研究，以优化支架。噻吩并[2，3-d]嘧啶，吡咯并[2，3-d]嘧啶的生物电子等排体，也探索了对RET抑制的影响。我们鉴定了一种先导化合物59，其显示出针对RET-wt和RET V804 M的低纳摩尔效力。另外59显示RET-CCDC 6驱动的LC-2/ad细胞的生长抑制。我们还确定了59是RET的2型抑制剂，并证明了其抑制肿瘤细胞迁移的能力。基于计算的研究，我们提出了一个结合位姿的59 RET口袋，并量化了其结合的个别残基的贡献。总之，59是一种重要的先导化合物，需要在生物学研究中进一步评价。
Gene fusions and point mutations of RET kinase are crucial for driving thoracic cancers, including thyroid cancer and non-small cell lung cancer. Various scaffolds based on different heterocycles have been synthesized and evaluated as RET inhibitors. In this work, we investigate pyrrolo[2,3-d]pyrimidine derivatives for inhibition of RET-wt, drug resistant mutant RET V804M and RET gene fusion driven cell lines. Several compounds were synthesized and the structure activity relationship was extensively studied to optimize the scaffold. Thieno[2,3-d]pyrimidine, a bioisostere of pyrrolo[2,3-d]pyrimidine, was also explored for the effect on RET inhibition. We identified a lead compound, 59, which shows low nanomolar potency against RET-wt and RET V804M. Further 59 shows growth inhibition of LC-2/ad cells which RET-CCDC6 driven. We also determined that 59 is a type 2 inhibitor of RET and demonstrated its ability to inhibit migration of tumor cells. Based on computational studies, we proposed a binding pose of 59 in RET pocket and have quantified the contributions of individual residues for its binding. Together, 59 is an important lead compound which needs further evaluation in biological studies.
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影响因子：
82.9
作者：
Kohno T;Ichikawa H;Totoki Y;Yasuda K;Hiramoto M;Nammo T;Sakamoto H;Tsuta K;Furuta K;Shimada Y;Iwakawa R;Ogiwara H;Oike T;Enari M;Schetter AJ;Okayama H;Haugen A;Skaug V;Chiku S;Yamanaka I;Arai Y;Watanabe S;Sekine I;Ogawa S;Harris CC;Tsuda H;Yoshida T;Yokota J;Shibata T
通讯作者：
Shibata T
影响因子：
6.3
作者：
BERENDSEN, HJC;VANDERSPOEL, D;VANDRUNEN, R
通讯作者：
VANDRUNEN, R
影响因子：
11.5
作者：
Asano, H;Toyooka, S;Shimizu, N
通讯作者：
Shimizu, N
影响因子：
4.2
作者：
Hatcher, John M.;Zhang, Jinwei;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
5.6
作者：
Kumari, Rashmi;Kumar, Rajendra;Lynn, Andrew
通讯作者：
Lynn, Andrew