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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: Machaon who wrote (22603)	6/23/1998 7:34:00 AM
From: Henry Niman	Respond to of 32384

Bob, I went the the University of Pittsburgh shortly after Progenx changed from a cancer diagnostic company to a cancer therapeutics company.

To: Machaon who wrote (22603)	6/23/1998 7:36:00 AM
From: Henry Niman	Respond to of 32384

Speaking of news, here's a recent abstract further describing interactions between RXR/RAR heterodimers and other nuclear proteins: Genes Dev 1998 Jun 1;12(11):1638-1651 The histone acetylase PCAF is a nuclear receptor coactivator. Blanco JCG, Minucci S, Lu J, Yang XJ, Walker KK, Chen H, Evans RM, Nakatani Y, Ozato K Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland 20892-2753 USA. [Medline record in process] Whereas the histone acetylase PCAF has been suggested to be part of a coactivator complex mediating transcriptional activation by the nuclear hormone receptors, the physical and functional interactions between nuclear receptors and PCAF have remained unclear. Our efforts to clarify these relationships have revealed two novel properties of nuclear receptors. First, we demonstrate that the RXR/RAR heterodimer directly recruits PCAF from mammalian cell extracts in a ligand-dependent manner and that increased expression of PCAF leads to enhanced retinoid-responsive transcription. Second, we demonstrate that, in vitro, PCAF directly associates with the DNA-binding domain of nuclear receptors, independently of p300/CBP binding, therefore defining a novel cofactor interaction surface. Furthermore, our results show that dissociation of corepressors enables ligand-dependent PCAF binding to the receptors. This observation illuminates how a ligand-dependent receptor function can be propagated to regions outside the ligand-binding domain itself. On the basis of these observations, we suggest that PCAF may play a more central role in nuclear receptor function than previously anticipated. PMID: 9620851, UI: 98283912

To: Machaon who wrote (22603)	6/23/1998 9:04:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Speaking of news, LGND is issuing a press release on Progesterone mimics, establishing a lead in the new Designer Progestins area.

To: Machaon who wrote (22603)	6/23/1998 9:13:00 AM
From: Henry Niman	Respond to of 32384

Yes, It came out at 9:00 AM

To: Machaon who wrote (22603)	6/23/1998 9:18:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's another earlier paper on progestin mimics: J Med Chem 1998 Jan 29;41(3):291-302 5-Aryl-1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal human progesterone receptor agonists. Zhi L, Tegley CM, Kallel EA, Marschke KB, Mais DE, Gottardis MM, Jones TK Department of Medicinal Chemistry, Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA. lzhi@ligand.com The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats. PMID: 9464360, UI: 98125636