Based on the little said at HnQ, it appears that Rigl's second proprietary program is in the E3 ubiquitin ligase pathway. E3 ligases are enzymes that mark/enable a protein for attachment by ubiquitin thereby further marking the protein for proteasome destruction. The lead molecule, undergoing tox studies now, is 4-6 months behind the asthma program (due into clinic '02), and has shown preclinical activity (in colon, 'as good as 5FU'; in lung cancer 'not quite as potent as Taxol, but potent'). Company says it is selective for tumor type and 'selective vs. other tissue too.' Justification for the target might be found in the footnotes to this paper.
Curr Opin Genet Dev 2002 Feb;12(1):86-91
The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity.
Baer R, Ludwig T.
Department of Pathology, Institute of Cancer Genetics, College of Physicians & Surgeons, Columbia University, 1150 St. Nicholas Avenue, 10032, New York, New York, USA
Although the protein product of the BRCA1 tumor suppressor gene has been implicated in a surprisingly diverse array of biological processes, the molecular mechanism by which BRCA1 loss promotes tumor formation remains unclear. Nonetheless, a pivotal advance has been achieved by recent studies that establish BRCA1 and its partner polypeptide BARD1 as enzymatic mediators of protein ubiquitination. The potent ubiquitin E3 ligase activity of the BRCA1/BARD1 heterodimer may be responsible for many of the biological properties attributed to BRCA1, including its ability to suppress tumor formation in normal cells.
Also : J Biol Chem 2001 May 4;276(18):14537-40 :
The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation.
Hashizume R, Fukuda M, Maeda I, Nishikawa H, Oyake D, Yabuki Y, Ogata H, Ohta T.
Division of Breast and Endocrine Surgery, St. Marianna University School of Medicine, Kawasaki, 216-8511 Japan.
BRCA1-BARD1 constitutes a heterodimeric RING finger complex associated through its N-terminal regions. Here we demonstrate that the BRCA1-BARD1 heterodimeric RING finger complex contains significant ubiquitin ligase activity that can be disrupted by a breast cancer-derived RING finger mutation in BRCA1. Whereas individually BRCA1 and BARD1 have very low ubiquitin ligase activities in vitro, BRCA1 combined with BARD1 exhibits dramatically higher activity. Bacterially purified RING finger domains comprising residues 1-304 of BRCA1 and residues 25-189 of BARD1 are capable of polymerizing ubiquitin. The steady-state level of transfected BRCA1 in vivo was increased by co-transfection of BARD1, and reciprocally that of transfected BARD1 was increased by BRCA1 in a dose-dependent manner. The breast cancer-derived BARD1-interaction-deficient mutant, BRCA1(C61G), does not exhibit ubiquitin ligase activity in vitro. These results suggest that the BRCA1-BARD1 complex contains a ubiquitin ligase activity that is important in prevention of breast and ovarian cancer development.
And also Genes Dev 1999 Jul 15;13(14):1822-33 :
The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity.
Lisztwan J, Imbert G, Wirbelauer C, Gstaiger M, Krek W.
Friedrich Miescher Institut, CH-4058 Basel, Switzerland.
pVHL, the product of the VHL tumor suppressor gene, plays an important role in the regulation of cell growth and differentiation of human kidney cells, and inactivation of the VHL gene is the most frequent genetic event in human kidney cancer. The biochemical function of pVHL is unknown. Here we report that pVHL exists in vivo in a complex that displays ubiquitination-promoting activity in conjunction with the universally required components E1, E2, and ubiquitin. pVHL-associated ubiquitination activity requires, at a minimum, pVHL to bind elongin C and Cul-2, relatives of core components of SCF (Skp1-Cdc53/Cul-1-F-box protein) E3 ligase complexes. Notably, certain tumor-derived mutants of pVHL demonstrate loss of associated ubiquitination promoting activity. These results identify pVHL as a component of a potential SCF-like E3 ubiquitin-protein ligase complex and suggest a direct link between pVHL tumor suppressor and the process of ubiquitination.
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