CX-4945 (Silmitasertib)

CX-4945 (Silmitasertib) is a potent and orally active casein kinase 2 (CK2) inhibitor with an IC₅₀ of 1nM for CK2α^[1]. CX-4945 has been used clinically to treat patients with T-cell prolymphocytic leukemia and cholangiocarcinoma^[2]. CX-4945 shows significant affinity for dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK 1A) and constitutively active glycogen synthase kinase-3β (GSK 3β), which are involved in Down syndrome phenotype, Alzheimer's disease, circadian clock regulation and diabetes^[3].

In vitro, treatment of MDA-MB-231 triple-negative breast cancer cells with CX-4945 (15-40μM) for 2h or 6h significantly increased the intracellular level of SALL2 protein (a tumor suppressor)^[4]. Treatment of parental and tamoxifen-resistant MCF-7 cells with CX-4945 (2.5, 5, 10μM) for 72h resulted in a concentration-dependent inhibition of cell proliferation and a significant suppression of tumor spheroid culture growth^[5].

In vivo, intraperitoneal injection of CX-4945 (25, 125mg/kg) for 24 days in mice bearing pancreatic ductal adenocarcinoma (PDAC) tissue xenografts from gemcitabine-resistant patients significantly enhanced the efficacy of gemcitabine, reduced tumor volume, and enhanced apoptosis in tumor tissue^[6].

References:
[1] Siddiqui-Jain A, Drygin D, Streiner N, et al. CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy[J]. Cancer research, 2010, 70(24): 10288-10298.
[2] D’Amore C, Borgo C, Sarno S, et al. Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy–potential clinical relevance[J]. Cellular Oncology, 2020, 43(6): 1003-1016.
[3] Grygier P, Pustelny K, Nowak J, et al. Silmitasertib (CX-4945), a clinically used CK2-kinase inhibitor with additional effects on GSK3β and DYRK1A kinases: a structural perspective[J]. Journal of medicinal chemistry, 2023, 66(6): 4009-4024.
[4] Hermosilla V E, Gyenis L, Rabalski A J, et al. Casein kinase 2 phosphorylates and induces the SALL2 tumor suppressor degradation in colon cancer cells[J]. Cell death & disease, 2024, 15(3): 223.
[5] Kim H, Elkins E, Islam R, et al. Silmitasertib (CX-4945) Disrupts ERα/HSP90 Interaction and Drives Proteolysis through the Disruption of CK2β Function in Breast Cancer Cells[J]. Cancers, 2024, 16(14): 2501.
[6] Liu Z D, Shi Y H, Xu Q C, et al. CSNK2A1 confers gemcitabine resistance to pancreatic ductal adenocarcinoma via inducing autophagy[J]. Cancer Letters, 2024, 585: 216640.

CX-4945 (Silmitasertib)是一种有效的具口服活性的酪蛋白激酶2（CK2）抑制剂，对CK2α的IC₅₀值为1nM^[1]。CX-4945已在临床上用于治疗T细胞幼淋巴细胞白血病和胆管癌患者^[2]。CX-4945对双特异性酪氨酸磷酸化调节激酶1A（DYRK 1A）和组成型活性糖原合成酶激酶-3β（GSK 3β）显示出显著的亲和力，参与唐氏综合征表型、阿尔茨海默病、昼夜节律钟调节和糖尿病^[3]。

在体外，CX-4945（15-40μM）处理MDA-MB-231三阴性乳腺癌细胞2h或6h，显著提高了细胞内的SALL2蛋白（一种肿瘤抑制因子）水平^[4]。CX-4945（2.5, 5, 10μM）处理亲本和他莫昔芬耐药MCF-7细胞72h，导以浓度依赖性方式抑制了细胞增殖，并显著抑制了肿瘤球状体培养物生长^[5]。

在体内，CX-4945（25, 125mg/kg）通过腹腔注射治疗吉西他滨耐药患者的胰腺导管腺癌（PDAC）组织异种移植小鼠24天，显著增强了吉西他滨的疗效，减少了肿瘤体积，增强了肿瘤组织细胞凋亡^[6]。