SB590885是一種有效的B-Raf抑制劑，K_i為0.16 nM，作用于B-Raf比作用于c-Raf選擇性高11倍，對(duì)其他人類(lèi)激酶沒(méi)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是一種有效的B-Raf抑制劑，無(wú)細(xì)胞試驗(yàn)中Ki為0.16 nM，作用于B-Raf比作用于c-Raf選擇性高11倍，對(duì)其他人類(lèi)激酶沒(méi)有抑制作用。

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

SB590885對(duì)B-Raf比對(duì)c-Raf 具有顯著更高的選擇性，K _i 分別為0.16 nM和1.72 nM。SB-590885是比之前描述的Raf/VEGFR激酶抑制劑BAY 439006 (對(duì)突變型B-Raf和c-Raf 的K _i 分別為38 nM 和6 nM)更有效的抑制劑。不同于多激酶抑制劑BAY43-9006，SB590885穩(wěn)定致癌B-Raf激酶域的活性結(jié)構(gòu)。在表達(dá)致癌B-RafV600E 的Colo205，HT29，A375P，SKMEL28，和MALME-3M細(xì)胞中，SB590885治療有效抑制ERK磷酸化，EC50分別為28 nM，58 nM，290 nM，58 nM，和190 nM，同樣的，抑制增殖的EC50分別為0.1 μM，0.87 μM，0.37 μM，0.12 μM，和0.15 μM。SB590885以BRAF突變體選擇性的方式減弱黑色素瘤細(xì)胞系的非貼壁依賴(lài)性生長(zhǎng)。 SB590885對(duì)B-Raf表現(xiàn)出高親和力，Kd為0.3 nM。大多數(shù)具有BRAF V600E突變體而缺乏CDK4突變體(451Lu，WM35，和WM983)的黑色素瘤細(xì)胞系對(duì)SB590885高度敏感，IC50 <1 μM。細(xì)胞周期素D1水平的增加是由于基因組擴(kuò)增介導(dǎo)的B-Raf V600E突變型黑色素瘤對(duì)SB590885產(chǎn)生的抗藥性。

在負(fù)荷突變體B-Raf表達(dá)的A375P黑色素瘤細(xì)胞異種移植物的小鼠體內(nèi)，SB590885給藥有效降低腫瘤發(fā)生，并適度抑制腫瘤生長(zhǎng)。