"helps when you've found those who would be your competitor."
OK, I've lost the thread here. I apologize if I'm being dense, but who are we talking about? The NCI guys? SKI guys? Did KOSN get rights to these other analogs (such as 17DMAG, I guess) or not?
"it's not as if we get any significant info about 17-AAG from KOSN itself, so I guess we need to keep looking ourselves."
>>Cancer Res. 2002 May 1;62(9):2478-82.
Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells.
Mabjeesh NJ, Post DE, Willard MT, Kaur B, Van Meir EG, Simons JW, Zhong H.
Winship Cancer Institute, Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor composed of alpha and beta subunits. HIF-1 is critically involved in cellular responses to hypoxia, glycolysis, and angiogenesis. Here, we show that treatment of prostate cancer PC-3 and LNCaP cells with the benzoquinone ansamycin geldanamycin, an Hsp90-specific inhibitor, induced degradation of HIF-1alpha protein in a dose- and time-dependent manner under both normoxia and hypoxia. This inhibition was also shown in other common cancer types tested. Rapid degradation of nuclear HIF-1alpha protein levels was accompanied by respective inhibition in HIF-1alpha functional transcription activity of VEGF. No difference between HIF-1alpha mRNA levels before or after geldanamycin treatment was found. Moreover, [35S]methionine pulse-chase analysis revealed that HIF-1alpha protein half-life was markedly decreased in the presence of geldanamycin compared with that in control. The geldanamycin-induced degradation of HIF-1alpha was reversed by proteosome inhibitors lactacystin and MG-132. We conclude that geldanamycin induces reduction of HIF-1alpha levels and its downstream transcriptional activity by accelerating protein degradation independent of O2 tension. Thus, benzoquinone ansamycin drugs and their derivatives, such as 17-allyl-aminogeldanamycin, are excellent candidates as small molecule drug inhibitors of HIF-1 overexpression in cancer cells.<<
HIF-1 is the subject of this free article at Nature Reviews:
nature.com
Cheers, Tuck |
