Degrasyn (WP1130)是一種選擇性的去泛素化酶(DUB: USP5， UCH-L1， USP9x， USP14， UCH37)抑制劑，也抑制Bcr/Abl，也是一種JAK2傳感器(不影響20S蛋白酶體)和轉(zhuǎn)錄激活劑(STAT)。In addition to inducing rapid down-regulation of Bcr/Abl without affecting Bcr or c-Abl, WP1130 also regulates the stability of Jak2 and c-Myc without affecting other kinases (HER1, HER2, c-Kit, FAK, ERK1, ERK2, Akt, Btk, Src and Src-related kinases) or transcription factors (wild-type p53, STAT1, STAT3, STAT5, c-Jun, NF-κB, and Max). Unlike adaphostin and Trisenox, WP1130 induces down-regulation of Bcr/Abl within 60 minutes. WP1130 is more effective in inducing apoptosis of myeloid and lymphoid tumor cells with IC50 of ~0.5-2.5 μM compared with normal CD34⁺ hematopoietic precursors, dermal fibroblasts, or endothelial cells with IC50 of ~5-10 μM. WP1130 (5 μM) specifically and rapidly down-regulates both wild-type and T315I mutant Bcr/Abl protein without affecting bcr/abl gene expression or engaging the proteasomal degradation pathway in chronic myelogenous leukemia (CML) cells, accompanied by induction of apoptosis. WP1130 is more effective in reducing leukemic cell colony formation compared with normal progenitor cells, and effective against primary leukemic cells harboring the T315I mutation. WP1130 induces rapid proteasomal-dependent degradation of c-Myc protein in MM-1 multiple myeloma and other tumor cell lines, correlated with tumor growth inhibition. Unlike AG490, WP1130 acts as a partly selective deubiquitinase (DUB) inhibitor to induce a rapid and marked accumulation of polyubiquitinated (K48/K63-linked) proteins into juxtanuclear aggresomes without affecting proteasome activity. WP1130 (5 μM) directly inhibits DUB activity of USP9x, USP5, USP14, UCH-L1, and UCH37, but not UCH-L3, resulting in downregulation of antiapoptotic and upregulation of proapoptotic proteins, such as MCL-1 and p53.Administration of WP1130 inhibits the growth of K562 tumors as well as both wildtype Bcr/Abl and T315I mutant Bcr/Abl-expressing BaF/3 cells transplanted into nude mice. Consistent with the down-regulation of c-Myc, WP1130 displays potent inhibitory activity against A375 melanoma tumors established in nude mice.WP1130 has an advantage over imatinib mesylate in that its activity is not inhibited by a variety of Abl kinase mutations, including T315I.Degrasyn (WP1130)是一種選擇性deubiquitinase (DUB: USP5，UCH-L1，USP9x，USP14，和 UCH37)抑制劑，對Bcr/Abl也有抑制作用，也是一種JAK2傳感器(不影響20S蛋白酶體)和轉(zhuǎn)錄激活劑(STAT)。Degrasyn (WP1130)可誘導(dǎo)凋亡而阻滯自噬。

Target	Value
DUB (Cell-free assay)
Bcr-Abl (Cell-free assay)	1.8 μM

除了誘導(dǎo)快速的Bcr/Abl下調(diào)而不影響B(tài)cr或c-Abl，WP1130也會調(diào)節(jié)Jak2和c-Myc的穩(wěn)定性，而不影響其他激酶(HER1，HER2，c-Kit，F(xiàn)AK，ERK1，ERK2，Akt，Btk，Src 和Src相關(guān)的激酶)或轉(zhuǎn)錄因子(野生型p53，STAT1，STAT3，STAT5，c-Jun，NF-κB，和Max)。不同于adaphostin 和Trisenox，WP1130在60分鐘內(nèi)誘導(dǎo)Bcr/Abl下調(diào)。與正常CD34在MM-1多發(fā)性骨髓瘤和其他腫瘤細胞系中，WP1130誘導(dǎo)快速的蛋白酶體依賴性c-Myc蛋白降解，與腫瘤生長的抑制相關(guān)。不同于AG490，WP1130作為一種部分選擇性去泛素化酶(DUB)抑制劑，誘導(dǎo)快速顯著的多泛素化(K48/K63連接)蛋白聚集到似核狀聚集體，而不影響蛋白酶體活性。WP1130 (5 μM)直接抑制除UCH-L3外的USP9x，USP5，USP14，UCH-L1，和UCH37的DUB活性，導(dǎo)致抗細胞凋亡的下調(diào)和促細胞凋亡蛋白質(zhì)，比如MCL-1和p53的增加。

WP1130給藥抑制移植到裸鼠體內(nèi)的K562腫瘤，以及野生型Bcr/Abl 和T315I突變體Bcr/Abl表達的BaF/3細胞的生長。與c-Myc的下調(diào)一致，WP1130對裸鼠體內(nèi)已建立的A375黑色素瘤表現(xiàn)出有效的抑制作用。