Characterization of Novel Derivatives of MBQ-167, an inhibitor of the GTP-binding proteins Rac/Cdc42.
Characterization of Novel Derivatives of MBQ-167, an inhibitor of the GTP-binding proteins Rac/Cdc42.
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DOI：
10.1158/2767-9764.crc-22-0303
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发表时间：
2022-12
期刊：
影响因子：
--
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中科院分区：
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Rac和CDC42是调节细胞迁移、侵袭和细胞周期进程的同源GTP酶，因此是转移治疗的关键靶点。我们之前曾报道过MBq-167的疗效，它同时阻断了乳腺癌细胞和小鼠转移模型中的rac1和CDc42。为了鉴定活性更高的化合物，合成了一组保持其9-ethyl-3-(1H-1，2，3-triazol-1-yl)-9H-carbazole核心的MBQ-167衍生物。与MBq-167类似，MBq-168和EHop-097抑制Rac和rac1B剪接变异体的激活，抑制乳腺癌细胞的存活，并诱导细胞凋亡。MBq-167和MBq-168通过干扰鸟嘌呤核苷酸结合来抑制RAC和CDC42，并且MBq-168是P21-激活的激酶(1-3)激活的更有效的抑制剂。EHop-097通过抑制鸟核苷酸交换因子Vav与Rac的相互作用，通过不同的机制发挥作用。MBq-168和EHop-097抑制转移性乳腺癌细胞的迁移，而MBq-168促进癌细胞极性的丧失，导致肌动蛋白细胞骨架的解体和与底物的脱离。在肺癌细胞中，MBq-168比MBq-167或EHop-097更有效地减少EGF引起的褶皱形成。与MBq-167相比，MBq-168显著抑制HER2阳性肿瘤的生长和肺、肝、脾转移。MBq-167和MBq-168均抑制细胞色素P450(CYP)酶3A4、2C9和2C19。然而，MBQ-168抑制CYP3A4的效力约为MBQ-167的10倍，从而证明了其在相关联合治疗中的有效性。综上所述，MBq-167衍生物MBq-168和EHop-097是另外两种具有相似和不同作用机制的有前景的抗肿瘤转移化合物。靶向调控肿瘤转移的相关GTP酶RAC和CDC42是阻止实体瘤转移的可行策略。在这里，我们描述了新的RAC和CDC42抑制剂，它们具有独特的作用机制，在不同的癌细胞系中具有不同的效力。MBq-167的衍生物MBq-168和EHop-097显示出作为潜在的抗转移癌症药物的前景。
Rac and Cdc42, are homologous GTPases that regulate cell migration, invasion, and cell-cycle progression; thus, representing key targets for metastasis therapy. We previously reported on the efficacy of MBQ-167, which blocks both Rac1 and Cdc42 in breast cancer cells and mouse models of metastasis. To identify compounds with increased activity, a panel of MBQ-167 derivatives was synthesized, maintaining its 9-ethyl-3-(1H-1,2,3-triazol-1-yl)-9H-carbazole core. Similar to MBQ-167, MBQ-168 and EHop-097 inhibit activation of Rac and Rac1B splice variant and breast cancer cell viability, and induce apoptosis. MBQ-167 and MBQ-168 inhibit Rac and Cdc42 by interfering with guanine nucleotide binding, and MBQ-168 is a more effective inhibitor of P21-activated kinase (1–3) activation. EHop-097 acts via a different mechanism by inhibiting the interaction of the guanine nucleotide exchange factor Vav with Rac. MBQ-168 and EHop-097 inhibit metastatic breast cancer cell migration, and MBQ-168 promotes loss of cancer cell polarity to result in disorganization of the actin cytoskeleton and detachment from the substratum. In lung cancer cells, MBQ-168 is more effective than MBQ-167 or EHop-097 at reducing ruffle formation in response to EGF. Comparable with MBQ-167, MBQ-168 significantly inhibits HER2-positive tumor growth and metastasis to lung, liver, and spleen. Both MBQ-167 and MBQ-168 inhibit the cytochrome P450 (CYP) enzymes 3A4, 2C9, and 2C19. However, MBQ-168 is approximately 10× less potent than MBQ-167 at inhibiting CYP3A4, thus demonstrating its utility in relevant combination therapies. In conclusion, the MBQ-167 derivatives MBQ-168 and EHop-097 are additional promising antimetastatic cancer compounds with similar and distinct mechanisms. Targeting the related GTPases Rac and Cdc42 that regulate cancer metastasis is a viable strategy to impede metastasis of solid cancers. Herein, we describe new Rac and Cdc42 inhibitors with unique mechanisms and varying potency in different cancer cell lines. The MBQ-167 derivatives MBQ-168 and EHop-097 show promise as potential antimetastatic cancer agents.
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DOI：
10.1074/jbc.m112.435941
发表时间：
2013-03-22
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Hong L;Kenney SR;Phillips GK;Simpson D;Schroeder CE;Nöth J;Romero E;Swanson S;Waller A;Strouse JJ;Carter M;Chigaev A;Ursu O;Oprea T;Hjelle B;Golden JE;Aubé J;Hudson LG;Buranda T;Sklar LA;Wandinger-Ness A
通讯作者：
Wandinger-Ness A
影响因子：
9
作者：
通讯作者：
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DOI：
10.1073/pnas.1216141110
发表时间：
2013-02-19
影响因子：
11.1
作者：
Kawazu, Masahito;Ueno, Toshihide;Mano, Hiroyuki
通讯作者：
Mano, Hiroyuki
影响因子：
6
作者：
Eiden C;Ungefroren H
通讯作者：
Ungefroren H
影响因子：
11.2
作者：
Maldonado MDM;Dharmawardhane S
通讯作者：
Dharmawardhane S