Liveblogging First-Time Disclosures From #ACSSanDiego
Mar24

Liveblogging First-Time Disclosures From #ACSSanDiego

Watch this space on Sunday as I cover the public unveiling of five drug candidates' structures. I’ll be liveblogging the “First Disclosures of Clinical Candidates” symposium at the San Diego ACS National Meeting, which runs from 2PM to 5PM Pacific. 1:30PM It's half an hour before the start of the session and the big ballroom is still pretty empty. Expect that to change in short order. 2:30PM LX4211 Company: Lexicon Pharmaceuticals Meant to treat: type 2 diabetes Mode of action: dual inhibitor of sodium glucose transporters 1 and 2, which play key roles in glucose absorption in the gastrointestinal tract and kidney Medicinal chemistry tidbits: this drug candidate had Lexicon's chemists refamiliarizing themselves with carbohydrate chemistry. Most inhibitors of sodium glucose transporters incorporate D-glucose in some way. Lexicon's chemists realized they could try something different-- inhibitors based on the scaffold of L-xylose, a non-natural sugar. The team has already published a J. Med. Chem paper (2009, 52, 6201–6204) explaining that strategy. LX4211 is a methyl thioglycoside-the team went with a methyl thioglycoside because upping the size too far beyond a methyl lost activity at SGLT1. Status in the pipeline: LX4211 is currently completing Phase IIb trials. 3:00PM BMS-927711 Company: Bristol-Myers Squibb Meant to treat: migraine Mode of action: antagonist of the receptor for calcitonin gene-related peptide- increased levels of this peptide have been reported in cases of migraine Medicinal chemistry tidbits: This team recently published an orally bioavailable CGRP inhibitor, BMS-846372 (ACS Med. Chem. Lett., DOI: 10.1021/ml300021s). However, BMS-846372 had limited aqueous solubility, something that might make its development challenging. To improve that solubility, the BMS team sought to add polar groups to their molecule, something that's been tough to do with CGRP inhibitors historically. In the end, the team managed to add a primary amine to BMS-846372's cycloheptane ring while maintaining CGRP activity, leading to BMS-927711. Status in the pipeline: Phase II clinical trials 3:05 lots of questions from the audience for this talk! One questioner notes (as was noted in talk) that 4 CGRP inhibitors had gone before this drug in the clinic, and not made it through. Speaker notes that this candidate is more potent than others at CGRP (27 picomolar). 3:53 We're a bit behind schedule but got plenty of good chemistry... GSK2636771 Company: GlaxoSmithKline Meant to treat: tumors with loss-of-function in the tumor suppressor protein PTEN (phosphatase and tensin homolog)- 2nd most inactivated tumor suppressor after p53- cancers where this is often the case include prostate and endometrial Mode of action: inhibitor of phosphoinositide 3-kinase-beta (PI3K-beta). Several lines of evidence suggest that proliferation in certain PTEN-deficient tumor cell lines is driven primarily by PI3K-beta....

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Haystack 2011 Year-in-Review
Jan03

Haystack 2011 Year-in-Review

Well, 2011 is in the books, and we here at The Haystack felt nostalgic for all the great chemistry coverage over this past year, both here and farther afield. Let’s hit the high points: 1. HCV Takes Off – New treatments for Hepatitis C have really gained momentum. An amazing race has broken out to bring orally available, non-interferon therapies to market. In October, we saw Roche acquire Anadys for setrobuvir, and then watched Pharmasset’s success with PSI-7977 prompt Gilead’s $11 billion November buyout.  And both these deals came hot on the heels of Merck and Vertex each garnering FDA approval for Victrelis and Incivek, respectively, late last spring. 2. Employment Outlook: Mixed – The Haystack brought bad employment tidings a few times in 2011, as Lisa reported. The “patent cliff” faced by blockbuster drugs, combined with relatively sparse pharma pipelines, had companies tightening their belts more than normal. Traffic also increased for Chemjobber Daily Pump Trap updates, which cover current job openings for chemists of all stripes. The highlight, though, might be his Layoff Project.  He collects oral histories from those who’ve lost their jobs over the past few years due to the pervasive recession and (slowly) recovering US economy.. The result is a touching, direct, and sometimes painful collection of stories from scientists trying to reconstruct their careers, enduring salary cuts, moves, and emotional battles just to get back to work. 3. For Cancer, Targeted Therapies – It’s also been quite a year for targeted cancer drugs. A small subset of myeloma patients (those with a rare mutation) gained hope from vemurafenib approval. This molecule, developed initially by Plexxikon and later by Roche / Daiichi Sankyo, represents the first success of fragment-based lead discovery, where a chunk of the core structure is built up into a drug with help from computer screening.From Ariad’s promising  ponatinib P2 data for chronic myeloid leukemia, to Novartis’s Afinitor working in combination with aromasin to combat resistant breast cancer. Lisa became ‘xcited for Xalkori, a protein-driven lung cancer therapeutic from Pfizer. Researchers at Stanford Medical School used GLUT1 inhibitors to starve renal carcinomas of precious glucose, Genentech pushed ahead MEK-P31K inhibitor combinations for resistant tumors, and Incyte’s new drug Jakifi (ruxolitinib), a Janus kinase inhibitor, gave hope to those suffering from the rare blood cancer myelofibrosis. 4. Sirtuins, and “Stuff I Won’t Work With  – Over at In the Pipeline, Derek continued to chase high-profile pharma stories. We wanted to especially mention his Sirtris / GSK coverage (we had touched on this issue in Dec 2010). He kept up with the “sirtuin saga” throughout 2011, from trouble with duplicating life extension in model organisms to the...

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