5-[2-[4-[2-(二甲基氨基)乙氧基]苯基]-5-(4-吡啶基)-1H-咪唑-4-基]-2,3-二氢-1-茚酮肟

SB590885是一种有效的B-Raf抑制剂，K_i为0.16 nM，作用于B-Raf比作用于c-Raf选择性高11倍，对其他人类激酶没有抑制作用。 SB590885 displays significant selectivity for B-Raf over c-Raf with K_i of 0.16 nM over 1.72 nM. SB-590885 is a more potent inhibitor than the previously described Raf/VEGFR kinase inhibitor BAY 439006 (K_i = 38 nM for mutant B-Raf, 6 nM for c-Raf). SB590885 displays potent selectivity over 46 other kinases. Unlike the multi-kinase inhibitor BAY43-9006, SB590885 stabilizes the oncogenic B-Raf kinase domain in an active configuration. In Colo205, HT29, A375P, SKMEL28, and MALME-3M cells expressing oncogenic B-RafV600E, SB590885 treatment potently inhibits ERK phosphorylation with EC50 of 28 nM, 58 nM, 290 nM, 58 nM, and 190 nM, respectively, and consistently, inhibits the proliferation with EC50 of 0.1 μM, 0.87 μM, 0.37 μM, 0.12 μM, and 0.15 μM, respectively. SB590885 decreases anchorage-independent growth of melanoma cell lines in a BRAF mutant-selective manner. SB590885 displays high affinity for B-Raf with Kd of 0.3 nM. Most of the melanoma cell lines that harbor the BRAF V600E mutation and lack CDK4 mutations (451Lu, WM35, and WM983) are highly sensitive to SB590885 with IC50 of <1 μM. Increased levels of cyclin D1 resulting from genomic amplification mediate SB590885 resistance in B-Raf V600E-mutated melanomas. Administration of SB590885 potently decreases tumorigenesis in murine xenografts established from mutant B-Raf-expressing A375P melanoma cells, and modestly inhibits tumor growth. SB590885 displays significant selectivity for B-Raf over c-Raf. SB590885是一种有效的B-Raf抑制剂，无细胞试验中Ki为0.16 nM，作用于B-Raf比作用于c-Raf选择性高11倍，对其他人类激酶没有抑制作用。

Target	Value
B-Raf (Cell-free assay)	0.16 nM(Ki)

SB590885对B-Raf比对c-Raf 具有显著更高的选择性，K _i 分别为0.16 nM和1.72 nM。SB-590885是比之前描述的Raf/VEGFR激酶抑制剂BAY 439006 (对突变型B-Raf和c-Raf 的K _i 分别为38 nM 和6 nM)更有效的抑制剂。不同于多激酶抑制剂BAY43-9006，SB590885稳定致癌B-Raf激酶域的活性结构。在表达致癌B-RafV600E 的Colo205，HT29，A375P，SKMEL28，和MALME-3M细胞中，SB590885治疗有效抑制ERK磷酸化，EC50分别为28 nM，58 nM，290 nM，58 nM，和190 nM，同样的，抑制增殖的EC50分别为0.1 μM，0.87 μM，0.37 μM，0.12 μM，和0.15 μM。SB590885以BRAF突变体选择性的方式减弱黑色素瘤细胞系的非贴壁依赖性生长。 SB590885对B-Raf表现出高亲和力，Kd为0.3 nM。大多数具有BRAF V600E突变体而缺乏CDK4突变体(451Lu，WM35，和WM983)的黑色素瘤细胞系对SB590885高度敏感，IC50 <1 μM。细胞周期素D1水平的增加是由于基因组扩增介导的B-Raf V600E突变型黑色素瘤对SB590885产生的抗药性。

在负荷突变体B-Raf表达的A375P黑色素瘤细胞异种移植物的小鼠体内，SB590885给药有效降低肿瘤发生，并适度抑制肿瘤生长。