Design, synthesis, and Structure-Activity Relationships (SAR) of 3-vinylindazole derivatives as new selective tropomyosin receptor kinases (Trk) inhibitors
Design, synthesis, and Structure-Activity Relationships (SAR) of 3-vinylindazole derivatives as new selective tropomyosin receptor kinases (Trk) inhibitors
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作为新型选择性原肌球蛋白受体激酶 (Trk) 抑制剂的 3-乙烯基吲唑衍生物的设计、合成和结构活性关系 (SAR)
DOI：
10.1016/j.ejmech.2020.112552
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发表时间：
2020-10-01
影响因子：
6.7
通讯作者：
Ding, Ke
中科院分区：
文献类型：
--
作者：
Duan, Yunxin;Wang, Jie;Ding, Ke
神经营养受体酪氨酸激酶(NTRK)融合是各种成人和儿童肿瘤的致癌驱动因素，美国FDA批准小分子Trk抑制剂Larotrectinib(1，LOXO-101)和entrectinib(2)进行了验证。然而，基因突变介导的耐药性成为Trk抑制剂治疗的主要挑战。本文报道了一系列新型低纳米分子势Trk抑制剂3-乙烯基咪唑类化合物的设计、合成及构效关系研究。具有代表性的化合物7Mb与Trita/B/C结合，K-d值分别为1.6、3.1和4.9 nM，并抑制它们的激酶功能，IC50值分别为1.6、2.9和2.0 nM，但在KINOMEcan选择性研究中，对403个野生型激酶中的大多数明显效力较低。该化合物还有效地抑制了一组稳定转化为NTRK融合基因的BaF3细胞的增殖，IC50值在低NM范围内。此外，该化合物对NTRK1-G667C和NTRK3-G696A突变的拉洛替尼耐药细胞有较强的抑制作用，IC50值分别为0.031和0.018微米。虽然7Mb相对较差的口服生物利用度将限制其进一步发展，但该化合物可能被用作进一步结构优化的先导分子。(C)2020年爱思唯尔·马森公司。版权所有。
Neurotrophic receptor tyrosine kinase (NTRK) fusions are oncogenic drivers for a variety of adult and pediatric tumors, validated by the US FDA approval of small molecular Trk inhibitors Larotrectinib (1, LOXO-101) and Entrectinib (2). However, gene mutation mediated resistance becomes a major challenge for Trk inhibitor therapies. Herein, we report the design, synthesis and Structure-Activity Relationship investigation of a series of 3-vinylindazole derivatives as new Trk inhibitors with low nanomolar potencies. A representative compound, 7mb, binds to TrItA/B/C with K-d values of 1.6, 3.1 and 4.9 nM, and suppresses their kinase functions with IC50 values of 1.6, 2.9 and 2.0 nM, respectively, but is obviously less potent for the majority of a panel of 403 wild-type kinases in a KINOMEscan selectivity investigation. The compound also potently suppresses proliferation of a panel of BaF3 cells stably transformed with NTRK fusions with IC50 values in low nM ranges. Additionally, the compound exhibits strong inhibition against the Larotrectinib-resistant cells with NTRK1-G667C or NTRK3-G696A mutations with IC50 values of 0.031 and 0.018 mu M, respectively. Although the relatively poor oral bioavailability of 7mb will limit its further development, this compound may be utilized a lead molecule for further structural optimization. (C) 2020 Elsevier Masson SAS. All rights reserved.