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R1530

R1530 is a pyrazolobenzodiazepine small molecule with potential antiangiogenesis and antineoplastic activities. R1530 is also a mitosis-angiogenesis inhibitor (MAI)  that inhibits multiple receptor tyrosine kinases involved in angiogenesis, such as vascular endothelial growth factor receptor (VEGFR)-1, -2, -3, platelet-derived growth factor receptor (PDGFR) beta‚ FMS-like tyrosine kinase (Flt)-3, and fibroblast growth factor receptor (FGFR) -1, -2. In addition, this agents exhibits anti-proliferative activity by initiating mitotic arrest and inducing apoptosis. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    R1530  is currently being developed by Hoffmann-La Roche Inc

Preclinical study of R1350 (data published in 2011):
Reclinical study showed that 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. 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. (source: Cancer Chemother Pharmacol. 2011 Dec;68(6):1585-94.).

1. Discovery of Orally Active Dual Acting Mitosis/Angiogenesis Inhibitor R1530 for the Treatment of Solid Tumors. Liu, Jin-Jun; Wovkulich, Peter; Ju, Grace; Carjaval, Daisy; Ding, Qingjie; Higgins, Brian; Kolinsky, Kenneth; Luk, Kin-Chun; Packman, Kathryn; Pizzolato, Giacomo; Tovar, Christian; Yi, Ren; Zhang, Zhuming. Discovery Chemistry, Hoffmann-La Roche Inc., Nutley, NJ, USA. Frontiers in CNS and Oncology Medicinal Chemistry, ACS-EFMC, Siena, Italy, October 7-9 (2007), COMC-043. Publisher: American Chemical Society, Division of Medicinal Chemistry, Washington, D. C CODEN: 69KAR2 Conference; Meeting Abstract; Online Computer File written in English. AN 2007:1171016 CAPLUS.

2. Kolinsky K, Tovar C, Zhang YE, Railkar A, Yang H, Carvajal D, Nevins T, Geng W, Linn M, Packman K, Liu JJ, Zhang Z, Wovkulich P, Ju G, Higgins B. Preclinical  evaluation of the novel multi-targeted agent R1530. Cancer Chemother Pharmacol. 2011 Dec;68(6):1585-94. Epub 2011 May 8. PubMed PMID: 21553286.

3. Process for preparing pyrazole functionalized benzodiazepinones Full Text By Harrington, Peter J.; Paulsen, Valerie Grace; Tucker, Charles E. From U.S. Pat. Appl. Publ. (2009), US 20090203901 A1 20090813.

4. Regimen of administration for 5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-methoxy-3-methyl-pyrazolo[3,4-b][1,4] benzodiazepine for the treatment of cancer Full Text By Mikulski, Stanislaw M. From PCT Int. Appl. (2007), WO 2007042430 A1 20070419.

5. Preparation of pyrazolobenzodiazepine derivatives as anticancer agents Full Text By Liu, Jin-Jun; Luk, Kin-Chun; Pizzolato, Giacomo; Ren, Yi; Thakkar, Kshitij Chhabilbhai; Wovkulich, Peter Michael; Zhang, Zhuming From U.S. Pat. Appl. Publ. (2006), US 20060079511 A1 20060413.