R1530

R1530 is a potent and orally active inhibitor of mitosis/angiogenesis [1].
Mitosis is a part of the cell cycle process by which chromosomes in a cell nucleus are separated into two identical sets with each in its own nucleus. Angiogenesis refers to the growth of new blood vessels and is an essential component in the progression and metastasis of tumors [1].
R1530 showed potent inhibitory activities against cyclin-dependent kinases, such as CDK2 and CDK4, and angiogenesis-related growth factor receptor, such as KDR, FGFr, PDGFr, and EGFr [1]. In a series of human tumor cell lines, R1530 inhibited the growth of cells with IC50 values ranging from 0.22 to 3.43 μM. Also, R1530 strongly inhibited human umbilical vein endothelial cells (HUVEC) growth driven by VEGF or bFGF with IC50 values of 49 nM and 118 nM, respectively [2].
In nude mice bearing human H460 tumor xenografts, R1530 (3 to 25 mg/kg, orally twice a day, 20 days) inhibited tumor growth in a dose-dependent way. R1530 (the 25 mg/kg dose) reduced tumor size by 58% in average [3].
References:
[1]. Liu JJ, Higgins B, Ju G, et al. Discovery of a highly potent, orally active mitosis/angiogenesis inhibitor r1530 for the treatment of solid tumors. ACS Med Chem Lett, 2013, 4(2): 259-263.
[2]. Kolinsky K, Tovar C, Zhang YE, et al. Preclinical evaluation of the novel multi-targeted agent R1530. Cancer Chemother Pharmacol, 2011, 68(6): 1585-1594.
[3]. Tovar C, Higgins B, Deo D, et al. Small-molecule inducer of cancer cell polyploidy promotes apoptosis or senescence: Implications for therapy. Cell Cycle, 2010, 9(16): 3364-3375.

Discovery of a highly potent, orally active mitosis/angiogenesis inhibitor r1530 for the treatment of solid tumors.[Pubmed:24900658]

ACS Med Chem Lett. 2013 Jan 15;4(2):259-63.

A new series of 7,8-disubstituted pyrazolobenzodiazepines based on the lead compound 1 have been synthesized and evaluated for their effects on mitosis and angiogenesis. Described herein is the design, synthesis, SAR, and antitumor activity of these compounds leading to the identification of R1530, which was selected for clinical evaluation.

Preclinical evaluation of the novel multi-targeted agent R1530.[Pubmed:21553286]

Cancer Chemother Pharmacol. 2011 Dec;68(6):1585-94.

PURPOSE: This study describes the antiproliferative activity of the multikinase inhibitor R1530 in vitro and its antitumor and anti-angiogenic activity, pharmacokinetics, and tolerability in vivo. METHODS: The antiproliferative activity of R1530 was investigated in a range of human tumor, endothelial and fibroblast cell lines. Tolerability and antitumor activity were assessed in mice bearing a range of human tumor xenografts, and anti-angiogenic properties were established in the murine corneal pocket assay. R1530 pharmacokinetics in mice were established. RESULTS: R1530 strongly inhibited human tumor cell proliferation. Growth factor-driven proliferation of endothelial and fibroblast cells was also inhibited. Significant tumor growth inhibition was demonstrated in a lung cancer xenograft model with a range of once daily, weekly and twice-weekly doses of R1530 (3.125-50 mg/kg qd, 100 mg/kg qw, 100 mg/kg biw). Daily doses were most effective in the lung cancer model and also had significant growth inhibitory effects in models of colorectal, prostate, and breast tumors. Tumor regression occurred in all models treated with the maximum tolerated daily dose (50 mg/kg). The doses of 25 and 50 mg/kg qd resulted in biologically significant increased survival in all tested models. After oral administration in nude mice, R1530 showed good tissue penetration. Exposure was dose dependent up to 100 mg/kg with oral administration. CONCLUSIONS: R1530 has demonstrated activity against a range of tumor models in vitro and in vivo and is an effective inhibitor of angiogenesis. These findings support the approach of targeting multiple pathways in the search for potential agents with improved anticancer properties.

Small-molecule inducer of cancer cell polyploidy promotes apoptosis or senescence: Implications for therapy.[Pubmed:20814247]

Cell Cycle. 2010 Aug 15;9(16):3364-75.

Polyploidy results from deregulated cell division and has been considered an undesirable event leading to increased mutation rate and cancer development. However, polyploidy may also render cancer cells more vulnerable to chemotherapy. Here, we identify a small-molecule inducer of polyploidy, R1530, which interferes with tubulin polymerization and mitotic checkpoint function in cancer cells, leading to abortive mitosis, endoreduplication and polyploidy. In the presence of R1530, polyploid cancer cells underwent apoptosis or became senescent which translated into potent in vitro and in vivo efficacy. Normal proliferating cells were resistant to R1530-induced polyploidy thus supporting the rationale for cancer therapy by induced polyploidy. Mitotic checkpoint kinase BubR1 was found downregulated during R1530-induced exit from mitosis, a likely consequence of PLK4 inhibition. BubR1 knockdown in the presence of nocodazole induced an R1530-like phenotype, suggesting that BubR1 plays a key role in polyploidy induction by R1530 and could be exploited as a target for designing more specific polyploidy inducers.