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.