Fumarranol, a Rearranged Fumagillin Analogue That Inhibits Angiogenesis in Vivo

The fumagillin family of natural products inhibits angiogenesis through the irreversible inhibition of the type 2 methionine aminopeptidase (MetAP2). Herein is reported a novel fumagillin analogue named fumarranol. It is shown that, like fumagillin, fumarranol selectively inhibits MetAP2 and endothelial cell proliferation. It is also active in a mouse model of angiogenesis in vivo. Unlike TNP-470, fumarranol does not covalently bind to MetAP2. Fumarranol may serve as a lead for a new class of angiogenesis inhibitors

Inhibition of Angiogenesis by the Antifungal Drug Itraconazole

Angiogenesis, the formation of new blood vessels, is implicated in a number of important human diseases, including cancer, diabetic retinopathy, and rheumatoid arthritis. To identify clinically useful angiogenesis inhibitors, we assembled and screened a library of mostly Food and Drug Administration-approved drugs for inhibitors of human endothelial cell proliferation. One of the most promising and unexpected hits was itraconazole, a known antifungal drug. Itraconazole inhibits endothelial cell cycle progression at the G1 phase in vitro and blocks vascular endothelial growth factor/basic fibroblast growth factor-dependent angiogenesis in vivo. In attempts to delineate the mechanism of action of itraconazole, we found that human lanosterol 14α-demethylase (14DM) is essential for endothelial cell proliferation and may partially mediate the inhibition of endothelial cells by itraconazole. Together, these findings suggest that itraconazole has the potential to serve as an antiangiogenic drug and that lanosterol 14DM is a promising new target for discovering new angiogenesis inhibitors

Identification of Type 1 Inosine Monophosphate Dehydrogenase as an Antiangiogenic Drug Target

To rapidly discover clinically useful angiogenesis inhibitors, we created and screened a library of existing drugs for inhibition of endothelial cell proliferation. Mycophenolic acid (MPA), an immunosuppressive drug, was found to potently inhibit endothelial cell proliferation in vitro and block tumor-induced angiogenesis in vivo. Using RNA interference, we found that knockdown of one of the two known isoforms of inosine monophosphate dehydrogenase (IMPDH-1) is sufficient to cause endothelial cell cycle arrest

Supplementary Figure 1 from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Pathways targeted by the Dana-Farber Targeted Therapy Collection and clinical development status</p

Supplementary Figure 4 from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Chemical structures of lead compounds</p

Supplementary figure legends from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Legends to the supplementary figures</p

Supplementary Figure 2 from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Comparison of compound libraries reported in ROS1 kinase screens</p

Supplementary file 1 from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Contents of the Dana-Farber Targeted Therapy Library and raw data</p

Supplementary Figure 3 from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Inhibition of Ba/F3 CD74-ROS1 proliferation</p

Supplementary Figure 5-7 from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Inhibition of ROS1 signaling in Ba/F3 and UMG-118 cells and the RNPC3-ROS1 fusion</p