Regorafenib

Regorafenib is an orally active multi-kinase inhibitor with IC₅₀ values of 13/4.2/46, 22, 7, 1.5 and 2.5nM for VEGFR1/2/3, PDGFRβ, Kit, RET and Raf-1, respectively^[1]. Regorafenib has good anti-tumor and anti-angiogenic activities^{[2, 3]}.

In vitro, Regorafenib (0-20μM) treatment of lung squamous cell carcinoma (LSCC) cell lines (NCI-H1703, NCI-H2170, SK-MES-1 cells) for 24-72h, inhibited cell proliferation in a dose- and time-dependent manner and induced cell G0/G1 phase arrest^[4]. Regorafenib (2.5-10μM) treatment of HepG2 cells for 24-96h, inhibited cell growth in a dose- and time-dependent manner, induced cell apoptosis, and increased the level of phosphorylated c-Jun^[5].

In vivo, oral treatment of mice with adrenal SK-N-SH neuroblastoma orthotopically implanted with Regorafenib (30mg/kg) for 14 days, significantly inhibited tumor growth in the mice, with the average final weight of the tumor in the control group being 2.16g and the average final weight of the tumor in the Regorafenib-treated group being only 0.35g^[6]. Oral treatment of mice with metastatic colon cancer model with Regorafenib (30mg/kg) for 14 days, inhibited tumor growth and metastasis in the mice, significantly reduced tumor angiogenesis, and significantly reduced the number of infiltrating macrophages^[7].

References:
[1] Wilhelm S M, Dumas J, Adnane L, et al. Regorafenib (BAY 73‐4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity[J]. International journal of cancer, 2011, 129(1): 245-255.
[2] Chen C H, Hsu F T, Chen W L, et al. Induction of apoptosis, inhibition of MCL-1, and VEGF-A expression are associated with the anti-cancer efficacy of magnolol combined with regorafenib in hepatocellular carcinoma[J]. Cancers, 2021, 13(9): 2066.
[3] Lim Y, Han S W, Yoon J H, et al. Clinical implication of anti-angiogenic effect of regorafenib in metastatic colorectal cancer[J]. PLoS One, 2015, 10(12): e0145004.
[4] Hu X, Wu L, Zhang Z, et al. The anti-tumor effect of regorafenib in lung squamous cell carcinoma in vitro[J]. Biochemical and Biophysical Research Communications, 2018, 503(2): 1123-1129.
[5] Carr B I, Cavallini A, Lippolis C, et al. Fluoro‐Sorafenib (Regorafenib) effects on hepatoma cells: growth inhibition, quiescence, and recovery[J]. Journal of cellular physiology, 2013, 228(2): 292-297.
[6] Subramonian D, Phanhthilath N, Rinehardt H, et al. Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways[J]. British journal of cancer, 2020, 123(4): 568-579.
[7] Abou-Elkacem L, Arns S, Brix G, et al. Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model[J]. Molecular cancer therapeutics, 2013, 12(7): 1322-1331.

Regorafenib是一种具口服活性的多激酶抑制剂，抑制VEGFR1/2/3，PDGFRβ，Kit，RET和Raf-1的IC₅₀值分别为13/4.2/46，22，7，1.5和2.5nM^[1]。Regorafenib具有良好的抗肿瘤和抗血管生成活性^{[2, 3]}。

在体外，Regorafenib（0-20μM）处理肺鳞状细胞癌（LSCC）细胞系（NCI-H1703、 NCI-H2170、SK-MES-1细胞）24-72h，以剂量和时间依赖性方式抑制了细胞增殖，诱导了细胞G0/G1期阻滞^[4]。Regorafenib（2.5-10μM）处理HepG2细胞24-96h，以剂量和时间依赖性方式抑制了细胞的生长，诱导了细胞凋亡，增加了磷酸化c-Jun的水平^[5]。

在体内，Regorafenib（30mg/kg）通过口服治疗接受了肾上腺SK-N-SH神经母细胞瘤原位移植的小鼠14天，显著抑制了小鼠体内肿瘤的生长，对照组肿瘤的平均最终重量为2.16g，Regorafenib治疗组肿瘤的平均最终重量仅为0.35g^[6]。Regorafenib（30mg/kg）通过口服治疗转移性结肠癌模型小鼠14天，抑制了小鼠体内肿瘤的生长和转移，显著减少了肿瘤血管形成，显著减少了浸润性巨噬细胞的数量^[7]。