发明名称 |
Small-molecule inhibitors of Rac1 in metastatic cancer cells |
摘要 |
A novel inhibitor of Rac activity based on the structure of the established Rac/Rac-GEF inhibitor NSC23766 is discloses. The compound EHop-016, with an IC50 of 1.1 μM, is a 100-fold more efficient inhibitor of Rac activity than NSC23766. EHop-016 is specific for Rac1 and Rac3 at concentrations ≦5 mM. At higher concentrations, EHop-016 inhibits the close homolog Cdc42. In MDA-MB-435 cells, EHop-016 (≦5 mM) inhibits the association of the Rac-GEF Vav2 with a nucleotide-free Rac1(G15A), which has a high affinity for activated GEFs. EHop-016 does not affect the association of the Rac-GEF Tiam-1 with Rac1(G15A) at similar concentrations. EHop-016 also inhibits the Rac activity of MDA-MB-231 metastatic breast cancer cells and reduces Rac-directed lamellipodia formation in both cell lines. EHop-016 decreases Rac-downstream effects of p21-activated kinase (PAK)1 activity and directed migration of metastatic cancer cells. At low concentrations (<5 μM), EHop-016 does not affect cell viability. |
申请公布号 |
US9278956(B1) |
申请公布日期 |
2016.03.08 |
申请号 |
US201414537755 |
申请日期 |
2014.11.10 |
申请人 |
University of Puerto Rico |
发明人 |
Hernandez Eliud;Vlaar Cornelis;Dharmawardhane Suranganie |
分类号 |
A61K31/506;C07D403/12;C07D413/14 |
主分类号 |
A61K31/506 |
代理机构 |
Hoglund & Pamias, PSC |
代理人 |
Hoglund & Pamias, PSC ;Rios Roberto J. |
主权项 |
1. A method of inhibiting human cancer cell metastasis comprising administering N4-(9-ethyl-9H-carbazol-3-yl)-N2-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine, having the following chemical structure: to a patient. |
地址 |
San Juan PR US |