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Alofanib (RPT835) Sale

(Synonyms: RPT835) 目录号 : GC32127

An allosteric inhibitor of FGFR2

Alofanib (RPT835) Chemical Structure

Cas No.:1612888-66-0

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10mM (in 1mL DMSO)
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5mg
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产品描述

Alofanib is an allosteric inhibitor of FGFR2.1,2 It inhibits FGF2-induced phosphorylation of FGFR substrate 2 (FRS2α) in KATO III gastric carcinoma cells (IC50 = <10 nM).2 Alofanib inhibits the growth of SKOV3 ovarian and Hs 578T breast cancer cells (GI50s = 370 and 210 nM, respectively). It inhibits proliferation of human umbilical vein endothelial cells (HUVECs) induced by basic FGF (bFGF; IC50 = 11 nM) and tube formation of SVEC4-10 endothelial cells when used at a concentration of 50 nM.1 It also inhibits migration of SVEC4-10 cells in a wound healing assay. Alofanib (50 mg/kg) decreases the number of microvessels in tumor tissue by 50% in a SKOV3 ovarian serous carcinoma mouse model. It reduces tumor growth in mouse xenograft models when administered at a dose of 30 mg/kg per day, and the degree of tumor volume reduction positively correlates with the expression level of FGFR22

1.Khochenkov, D.A., Solomko, E.S., Peretolchina, N.M., et al.Antiangiogenic activity of alofanib, an allosteric inhibitor of fibroblast growth factor receptor 2Bull. Exp. Biol. Med.160(1)84-87(2015) 2.Tsimafeyeu, I., Ludes-Meyers, J., Stepanova, E., et al.Targeting FGFR2 with alofanib (RPT835) shows potent activity in tumour modelsEur. J. Cancer6120-28(2016)

Chemical Properties

Cas No. 1612888-66-0 SDF
别名 RPT835
Canonical SMILES O=C(O)C1=CC=CC(S(=O)(NC2=CC(C3=CC=CN=C3)=C(C)C=C2[N+]([O-])=O)=O)=C1
分子式 C19H15N3O6S 分子量 413.4
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1 mM 2.419 mL 12.0948 mL 24.1896 mL
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Research Update

Targeting FGFR2 with Alofanib (RPT835) shows potent activity in tumour models

Eur J Cancer 2016 Jul;61:20-8.PMID:27136102DOI:10.1016/j.ejca.2016.03.068.

Alofanib (RPT835) is a novel selective allosteric inhibitor of fibroblast growth factor receptor 2 (FGFR2). We showed previously that alofanib could bind to the extracellular domain of FGFR2 and has an inhibitory effect on FGF2-induced phoshphorylation of FRS2α. In the present study, we further showed that alofanib inhibited phosphorylation of FRS2α with the half maximal inhibitory concentration (IC50) values of 7 and 9 nmol/l in cancer cells expressing different FGFR2 isoforms. In a panel of four cell lines representing several tumour types (triple-negative breast cancer, melanoma, and ovarian cancer), alofanib inhibited FGF-mediated proliferation with 50% growth inhibition (GI50) values of 16-370 nmol/l. Alofanib dose dependently inhibited the proliferation and migration of human and mouse endothelial cells (GI50 11-58 nmol/l) compared with brivanib and bevacizumab. Treatment with alofanib ablated experimental FGF-induced angiogenesis in vivo. In a FGFR-driven human tumour xenograft model, oral administration of alofanib was well tolerated and resulted in potent antitumour activity. Importantly, alofanib was effective in FGFR2-expressing models. These results show that alofanib is a potent FGFR2 inhibitor and provide strong rationale for its evaluation in patients with FGFR2-driven cancers.

Alofanib, an allosteric FGFR2 inhibitor, has potent effects on ovarian cancer growth in preclinical studies

Invest New Drugs 2017 Apr;35(2):127-133.PMID:27812884DOI:10.1007/s10637-016-0404-1.

Purpose Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity. We investigated antitumor activity of Alofanib (RPT835), a novel allosteric FGFR2 inhibitor, in ovarian cancer in vitro and in vivo. Methods Equal amounts of ovarian cancer cell (SKOV3) lysates were analyzed for FGFR1-3 protein expression using Wes. To assess the efficacy of alofanib on FGF-mediated cell proliferation, SKOV3 cells were incubated and were treated with serially diluted alofanib. Basic FGF was added at a concentration of 25 ng/ml. Control wells were left untreated. Cell growth inhibition was determined using Promega's Cell Titer-Glo® assay. Immunocompromised mice were used for xenotransplantation of SKOV3 cancer cells. Seventy animals with measurable tumors were selected on day 10 and randomized into control groups (no treatment or chemotherapy alone (paclitaxel + carboplatin) and treatment groups (alofanib orally or intravenously (different dose levels) in combination with chemotherapy). Measurements of tumor volume (mm3) were performed by digital calipers every 3 days during 31 days after tumor inoculation. Number of tumor vessels and Ki-67 index were calculated. Results SKOV3 cells express FGFR1 and FGFR2 but not FGFR3. Basic FGF increased proliferation of the ovarian cancer cells in untreated control group (P = 0.001). Alofanib inhibited growth of FGFR2-expressing SKOV3 cells with GI50 value of 0.37 μmol/L. Treatment with alofanib in combination with paclitaxel/carboplatin resulted in tumor growth delay phenotype in all treatment groups compared to control non-treatment groups. Compound exhibited a dose-dependent effect on tumor growth. Daily intravenous regimen of alofanib (total maximum dose per week was 350 mg/kg) demonstrated significant effect (inhibiting growth by 80 % and by 53 % in comparison with vehicle and chemotherapy group alone, respectively (P < 0.001). Alofanib decreased number of vessels in tumor (-49 %; P < 0.0001) and number of Ki-67-positive SKOV3 cells (-42 %, P < 0.05). There were tumor necrosis and cell degeneration in alofanib group. Conclusions We suggest that FGFR2 inhibition has potent effects on ovarian cancer growth in preclinical studies.

Molecular Modeling, de novo Design and Synthesis of a Novel, Extracellular Binding Fibroblast Growth Factor Receptor 2 Inhibitor Alofanib (RPT835)

Med Chem 2016;12(4):303-17.PMID:26732115DOI:10.2174/1573406412666160106154726.

Background: Fibroblast growth factor (FGF) receptors (FGFRs) play a key role in tumor growth and angiogenesis. The present report describes our search for an extracellularly binding FGFR inhibitor using a combined molecular modeling and de novo design strategy. Methods: Based upon crystal structures of the receptor with its native ligand and knowledge of inhibiting peptides, we have developed a computational protocol that predicts the putative binding of a molecule to the extracellular domains of the receptor. This protocol, or scoring function, was used in combination with the de novo synthesis program 'SYNOPSIS' to generate high scoring and synthetically accessible compounds. Results: Eight compounds belonging to 3 separate chemical classes were synthesized. One of these compounds, Alofanib (RPT835), was found to be an effective inhibitor of the FGF/FGFR2 pathway. The preclinical in vitro data support an allosteric inhibition mechanism of RPT835. RPT835 potently inhibited growth of KATO III gastric cancer cells expressing FGFR2, with GI50 value of 10 nmol/L. Conclusion: These results provide strong rationale for the evaluation of compound in advanced cancers.

Antiangiogenic Activity of Alofanib, an Allosteric Inhibitor of Fibroblast Growth Factor Receptor 2

Bull Exp Biol Med 2015 Nov;160(1):84-7.PMID:26597690DOI:10.1007/s10517-015-3104-5.

Alofanib is a potential allosteric inhibitor of FGFR2 used in oncology. The inhibitor blocks the extracellular part of the receptor and prevents its binding with the ligand. Alofanib suppressed proliferation of endothelial cells, their migration activity, and ability to form vessellike structures in vitro and significantly decreased the number of microvessels in Matrigel implant and in ovarian cancer (SKOV-3) xenograft in vivo. The results indicate that Alofanib can inhibit angiogenesis.

A phase 1b study of the allosteric extracellular FGFR2 inhibitor Alofanib in patients with pretreated advanced gastric cancer

Invest New Drugs 2023 Mar 13.PMID:36907947DOI:10.1007/s10637-023-01340-z.

Alofanib is a small-molecule allosteric extracellular FGFR2 inhibitor. We report safety and preliminary efficacy from the first-in-human phase 1b study of Alofanib in heavily pretreated patients with advanced gastric cancer. The standard dose-escalation design 3+3 aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Alofanib was administered daily intravenously 5 days on, 2 days off. There were five dose levels (50-350 mg/m2). All patients received Alofanib until disease progression or unacceptable toxicity. 21 patients were enrolled. Patients were predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 19% had ECOG PS 2, and were heavily pretreated (86% had previous 2 and more treatment lines). During dose escalation, no dose-limiting toxicities were observed, and MTD was not defined. 15 (71.4%) patients had at least one adverse event associated with the treatment (TRAE). Grade 3 or higher TRAEs were observed in 6 patients (28.6%). The most common TRAEs included reactions immediately after administration, diarrhea, thrombocytopenia, arthralgia, and headache. The median progression-free survival and overall survival was 3.63 (95% CI 1.58-5.68) and 7.0 (95% CI 3.82-10.18) months, respectively. The 6- and 12-month overall survival rates were 57.1% and 33.3%. Disease control rate was 68% with one durable partial response. The MTD has not been reached and dose of 350 mg/m2, 5 days on, 2 days off has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. (ClinicalTrials.gov identifier: NCT04071184).