Inhibition of tumor-microenvironment interaction and tumor invasion by small-molecule allosteric inhibitor of DDR2 extracellular domain.
Inhibition of tumor-microenvironment interaction and tumor invasion by small-molecule allosteric inhibitor of DDR2 extracellular domain.
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DOI：
10.1073/pnas.1805020115
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发表时间：
2018-08-14
影响因子：
11.1
通讯作者：
Longmore GD
中科院分区：
文献类型：
--
作者：
Grither WR;Longmore GD
为了有效地防止癌症从原发肿瘤部位扩散，新的治疗方法需要同时靶向肿瘤细胞、肿瘤环境中的细胞和细胞外基质以及这些部位之间的通信途径。胶原蛋白受体盘状结构域受体2（DDR2）已经被认为是这样的靶点。在这里，我们描述了DDR2的小分子抑制剂的鉴定和表征，其独特地通过细胞外结构域以变构方式起作用，以选择性地抑制DDR2在肿瘤细胞和肿瘤间质癌相关成纤维细胞中的作用。在乳腺癌实验小鼠模型中，WRG-28抑制DDR2信号传导和肿瘤细胞侵袭。已确定胶原结合受体酪氨酸激酶（RTK）盘状结构域受体2（DDR2）在肿瘤和肿瘤基质细胞中的作用对于乳腺癌转移至关重要。靶向RTK的胞外结构域的小分子抑制剂是罕见的，因为它们通常被认为太小而不能阻断与大的多肽配体的结合。在这里，我们报告的识别和表征的选择性，细胞外作用的小分子抑制剂（WRG-28）的DDR2，独特地抑制受体-配体相互作用，通过受体的变构调节。通过靶向DDR2，WRG-28抑制肿瘤侵袭和迁移，以及基质的肿瘤支持作用，并抑制转移性乳腺肿瘤细胞在肺部的定植。这些发现代表了一种抑制肿瘤-基质相互作用的方法，并支持DDR2的变构抑制剂如WRG-28的开发，作为一种有前途的抗转移治疗方法。
To effectively prevent cancer spread from primary tumor sites, new treatments need to target tumor cells, the cells and extracellular matrix within the tumor environment, and communicating pathways between these sites simultaneously. The collagen receptor discoidin domain receptor 2 (DDR2) has been implicated as such a target. Here, we describe the identification and characterization of a small molecule inhibitor of DDR2 that uniquely acts in an allosteric manner via the extracellular domain to selectively inhibit the action of DDR2 in tumor cells and tumor stromal cancer-associated fibroblasts. In experimental mouse models of breast cancer, WRG-28 inhibits DDR2 signaling and tumor cell invasion. The action of the collagen binding receptor tyrosine kinase (RTK) discoidin domain receptor 2 (DDR2) in both tumor and tumor stromal cells has been established as critical for breast cancer metastasis. Small molecule inhibitors that target the extracellular domain of RTKs are rare, as they have classically been regarded as too small to block binding with large polypeptide ligands. Here, we report the identification and characterization of a selective, extracellularly acting small molecule inhibitor (WRG-28) of DDR2 that uniquely inhibits receptor–ligand interactions via allosteric modulation of the receptor. By targeting DDR2, WRG-28 inhibits tumor invasion and migration, as well as tumor-supporting roles of the stroma, and inhibits metastatic breast tumor cell colonization in the lungs. These findings represent an approach to inhibiting tumor–stromal interactions and support the development of allosteric inhibitors of DDR2, such as WRG-28, as a promising approach to antimetastasis treatment.
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DOI：
10.1016/j.str.2009.10.012
发表时间：
2009-12-09
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Carafoli F;Bihan D;Stathopoulos S;Konitsiotis AD;Kvansakul M;Farndale RW;Leitinger B;Hohenester E
通讯作者：
Hohenester E
影响因子：
5.7
作者：
Carafoli, Federico;Mayer, Marie Cathrin;Shiraishi, Kazushige;Pecheva, Mira Anguelova;Chan, Lai Yi;Nan, Ruodan;Leitinger, Birgit;Hohenester, Erhard
通讯作者：
Hohenester, Erhard
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
影响因子：
28.2
作者：
Hammerman PS;Sos ML;Ramos AH;Xu C;Dutt A;Zhou W;Brace LE;Woods BA;Lin W;Zhang J;Deng X;Lim SM;Heynck S;Peifer M;Simard JR;Lawrence MS;Onofrio RC;Salvesen HB;Seidel D;Zander T;Heuckmann JM;Soltermann A;Moch H;Koker M;Leenders F;Gabler F;Querings S;Ansén S;Brambilla E;Brambilla C;Lorimier P;Brustugun OT;Helland A;Petersen I;Clement JH;Groen H;Timens W;Sietsma H;Stoelben E;Wolf J;Beer DG;Tsao MS;Hanna M;Hatton C;Eck MJ;Janne PA;Johnson BE;Winckler W;Greulich H;Bass AJ;Cho J;Rauh D;Gray NS;Wong KK;Haura EB;Thomas RK;Meyerson M
通讯作者：
Meyerson M
影响因子：
6
作者：
Conklin, Matthew W.;Eickhoff, Jens C.;Keely, Patricia J.
通讯作者：
Keely, Patricia J.