BDP9066 is a selective inhibitor of myotonic dystrophy-associated Cdc42-binding kinase (MRCK), with an IC50 of 64nM for MRCKβ and Ki values of 0.0136nM and 0.0233nM for MRCKα/β in SCC12 cells[1]. MRCK is a protein kinase that acts downstream of Cdc42. After being activated by Cdc42, MRCK promotes actin polymerization, stress fiber formation and cell membrane binding by phosphorylating downstream molecules such as myosin light chain 2 (MLC2), LIM domain kinase (LIMK), and myosin phosphatase target 1 (MYPT1)[2]. BDP9066 can be applied to the study of triple-negative breast cancer (TNBC), high-grade serous ovarian carcinoma (HGSC), and glioblastoma (GBM), and is a potential cancer chemotherapy drug[3].
In vitro, treatment of E2 and G7 cell lines with 250μM BDP9066 for 2 hours disrupted the actin-myosin cytoskeleton, inducing abnormal cell morphology to inhibit migration[4]. Treatment of HGSOC cells with 1μM BDP9066 for 24 hours increased the level of cleaved PARP in the cells, inhibited cell growth, induced apoptosis, and inhibited local adhesion signals, thereby impairing the globular formation of HGSOC cells[5]. In in vitro kinase assays, the EC50 values of BDP9066 for MRCKα and MRCKβ were 65nM and 72nM, respectively[5].
In vivo, when FVB mice were treated with BDP9066 (50μL; 80% (v/v) in DMSO; administered 4 times over 2 days) through skin application, the drug level in the skin of the mice was significantly higher than that in the blood, and the total tumor volume and mean papillary volume were significantly reduced, but the total number of papillomas was not different from that in the control group[1]. When mice carrying U87MG or G7 intracranial tumors were treated with BDP9066 (5mg/kg; twice daily; Monday to Friday; 4 weeks; subcutaneous injection), the tumor cell infiltration in the contralateral hemisphere of the irradiated mice treated with BDP9066 was not increased compared with the increase in the number of GBM cells in the contralateral hemisphere of the control mice after irradiation with 3 × 2 Gy[4].
References:
[1]. Unbekandt M, Belshaw S, Bower J, et al. Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer[J]. Cancer research, 2018, 78(8): 2096-2114.
[2]. Yamaguchi H, Chang L C, Chang O S S, et al. MRCK as a potential target for claudin-low subtype of breast Cancer[J]. International Journal of Biological Sciences, 2024, 20(1): 1.
[3]. McKinnon H J, Birch J, McDonald L, et al. A novel small molecule inhibitor of MRCK shows utility in blocking radiation induced invasion of glioblastoma cells in vitro and in vivo[J]. Cancer Research, 2018, 78(13_Supplement): 1933-1933.
[4]. Birch J L, Strathdee K, Gilmour L, et al. A novel small-molecule inhibitor of MRCK prevents radiation-driven invasion in glioblastoma[J]. Cancer research, 2018, 78(22): 6509-6522.
[5]. Kurimchak A M, Herrera-Montávez C, Brown J, et al. Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma[J]. Science signaling, 2020, 13(619): eaax8238.
BDP9066是一种选择性的肌强直性营养不良激酶相关的Cdc42结合激酶（MRCK）抑制剂，在SCC12细胞中对MRCKβ的IC50为64nM，对MRCKα/β的Ki值分别为0.0136nM和0.0233nM[1]。MRCK是一种蛋白激酶，作用于Cdc42的下游。在被Cdc42激活后，MRCK通过磷酸化下游分子如肌球蛋白轻链2（MLC2）、LIM结构域激酶（LIMK）和肌球蛋白磷酸酶靶基1（MYPT1），促进肌动蛋白聚合、应力纤维形成及结合细胞膜[2]。BDP9066能够应用于三阴性乳腺癌（TNBC）、卵巢高级别浆液性癌（HGSC）和胶质母细胞瘤（GBM）等研究，是一种潜在的癌症化疗药物[3]。
在体外，250μM的BDP9066处理E2和G7细胞系2小时，破坏了肌动蛋白-肌球蛋白细胞骨架，诱导异常细胞形态以抑制迁移[4]。用1μM BDP9066处理HGSOC细胞24h，细胞中切割PARP水平升高，细胞生长受阻，诱导细胞凋亡，并抑制局部粘附信号，从而损害HGSOC细胞的球状形成[5]。在体外激酶实验中，BDP9066对MRCKα和MRCKβ的EC50值分别为65nM和72nM[5]。
在体内，BDP9066（50μL；80%（v/v）in DMSO；两天内施用4次）皮肤涂抹处理FVB小鼠，小鼠皮肤中药物水平显著高于血液，总肿瘤体积和平均乳头状体体积均显著减少，但总乳头瘤数目和对照组相比无差异[1]。BDP9066（5mg/kg；每日两次，周一至周五；4周；皮下注射）处理携带U87MG或G7颅内成瘤小鼠，在小鼠接受3 × 2Gy辐照后，相比于对照小鼠对侧半球的GBM细胞数量增加的情况，用BDP9066治疗的受辐照小鼠对侧半球的肿瘤细胞浸润没有增加[4]。