#ChemCoach Carnival: From Big Pharma to Non-Profit

We’re almost at the end of National Chemistry week, folks, and the Haystack is finally kicking in to blogger SeeArrOh’s now rampant #ChemCoach carnival. The goal of any carnival is to get a lot of different bloggers to post on the same topic–in this case, to write about how they got to where they are today as a way of educating young chemists on their career options. Round-ups of the dozens of posts this week can be found here, here, and here. Since the science writing field has been well covered here and by our own Carmen Drahl, and because the Haystack is focused on all things pharma, I thought I’d enlist the help of someone with a much more illustrious career than my own. Without further ado, I give you some words of career wisdom from TB Alliance‘s chemistry guru Christopher Cooper: Your current job.   I’m Senior Director of Chemistry at the Global Alliance for TB Drug Development (TB Alliance), a non-profit, product development partnership headquartered in New York City.  My job encompasses all chemistry activities for the Alliance from early-, mid-, and late-stage drug discovery right through drug substance/API manufacturing for clinical trials.  The TB Alliance is dedicated to identifying safe, novel chemical entities for the rapid treatment of tuberculosis worldwide, and my job is to oversee the Alliance’s chemistry needs to achieve our goals (seewww.tballiance.org for more details). What you do in a standard “work day.”   Define “standard” … oh, and define “work day,” as well, please? All kidding aside, working for a small (~45 employees), entrepreneurial, research and development organization means that every day is truly different, whether it’s engaged in project team discussions with collaborators in Chicago and Belgium, or proposing new analogues/chemical series to pursue with chemists in Auckland or Seoul!  In fact, as we engage chemists (medicinal, process, manufacturing) on TB Alliance projects around the globe, my work “day” doesn’t really begin or end.  After all, if it’s 9:00 P.M. on the East Coast, it’s already 9:00 A.M. in Beijing!  Fortunately, the virtual nature of our business model translates into my own flexibility in addressing issues wherever and whenever they occur … and I don’t have to wash my glassware anymore (yey!). What kind of schooling / training / experience helped you get there?   In many ways, my background would appear fairly conventional, despite the more unconventional nature of my current position.  I received my B.S. from Clemson University in 1980, and my M.S. (1982) and Ph.D.’s (1988) from Stanford.  Having worked briefly in the pharmaceutical industry (CIBA-Geigy from 1982-1984), I was eager to return so I accepted a position...

Read More
TEDMED: Andrew Read’s Five Tips For Keeping Superbugs At Bay
Apr13

TEDMED: Andrew Read’s Five Tips For Keeping Superbugs At Bay

Researchers may like to think they’re pretty smart, but you could argue that bacteria have also got some bragging rights. Every day, microbes develop resistance to even the most powerful antibiotics scientists have developed. Andrew Read thinks evolution is the best lens for staring down the superbugs. He took the stage Thursday at TEDMED, where he warned, “we’re picking a fight with natural selection.” “Picking a fight without Darwin is like going to the moon without Newton,” Read added. “We are in the dark ages when it comes to evolutionary management.” Read, director of Penn State University’s Center for Infectious Disease Dynamics, sat down with me on Thursday and shared a few principles he thinks the scientific community should keep in mind in order to keep antibiotic resistance in check. Here are his five tips for would-be superbug slayers. Get smart with the drugs you’ve already got. “We can’t rely on a continual supply of new drugs,” Read said. Many firms have already exited antibiotic research, he notes. “You can see that the markets aren’t good enough right now to drive innovation,” since new antibiotics are precious and used only for patients’ most severe infections rather than being prescribed widely. Read says firms should continually evaluate dosing and combination strategies with established drugs in order to stave off resistance. “I’m not saying we shouldn’t discover new antimicrobials,” Read stressed. “In some situations, like malaria, it’s really critical. But we don’t want to put all our eggs in that basket.” Learn from what works. “I think magic bullets are the exception rather than the rule,” Read says. But researchers should focus on why wildly successful therapies were so. “Why was that pathogen unable to get around the smallpox vaccine? Why is chloroquine still working against some malarias in some parts of the world when it’s has failed miserably in others?” Read asked. Make the right matches for combination therapies. Read notes that some antimalarial drug combinations have consisted of drugs with markedly different half-lives. In effect, once the first drug has left the human body, all that’s left is the other drug, a monotherapy. “And that’s dangerous,” a breeding ground for resistance, Read cautions. “You want to be combining drugs that have similar half-lives.” Researchers should also think about whether their antibiotics become more lethal to microbes when used in combination, or less lethal, Read says. Evidence suggests that less lethal is better, he says. According to work from Roy Kishony’s lab at Harvard Medical School, if an antibiotic combo is less lethal, once resistance develops to one drug (call it drug A) in the pair, then drug B can...

Read More
Antibacterial Resistance – Learning Bacterial Tricks
Mar23

Antibacterial Resistance – Learning Bacterial Tricks

Virulent bacteria are growing increasingly resilient against our best antibiotics. Each day seems to bring a new story: MRSA outbreaks, resistant salmonella, or tough-to-treat tuberculosis. Just last week, World Health Organization director-general Dr. Margaret Chan delivered an address in Copenhagen, where she cautioned: “We are losing our first-line antimicrobials . . . in terms of replacement antibiotics, the pipeline is virtually dry. The cupboard is nearly bare.” (Click here for The Haystack’s past coverage of the development of new antibacterials). Why have our drugs stopped working? Recent research from St. Jude’s (Science, 2012, 1110) attempted to answer that question. Using X-ray crystallography, a technique used to see structures at the atomic level, the researchers were able to capture a critical moment when a drug binds to DHPS, its bacterial enzyme target. The scientists could then predict how bacteria evolve to dodge further biocidal bullets. The antibacterial medicines caught in the act by the St. Jude’s researchers are the sulfa drugs (see right), former front-line treatments many doctors push to the bottom of treatment regimens, due to increasingly resistant bacterial strains. Researchers knew resistance had something to do with the drugs’ mechanism of action; sulfa drugs mimic the binding of PABA – para-aminobenzoic acid, a compound found in many sunscreens (Chemical Note: PABA occurs naturally as bacterial vitamin H1, and can also be found in yeast and plants. Chemists often borrow naturally-occurring compounds for industrial uses; two prominent examples are vanillin and Vitamin C). Disruption of this PABA binding shuts down bacterial DNA replication, stopping reproduction. Before now, however, no one had succeeded in growing crystals of the active site that actually showed the drugs interacting with the enzymatic intermediate. Let’s take one more step back: how does PABA attach itself? The enzyme we’re discussing, DHPS, catalyzes bond formation between PABA and intermediates known as pterins (see picture, left). Earlier researchers believed that this molecular hook-up operated by an SN2 mechanism, a reaction where the PABA kicks out a small piece of the pterin to form a new C-N bond. We chemists would say that SN2 means concerted bond formation, meaning that PABA would bind at the same time as the leaving group (OPPi), well, leaves. Turns out that picture’s not quite right: it’s more SN1-like, which means that the pterin first forms a positively-charged, enzyme-stabilized species! As you can imagine, this is no small feat, since the reaction works at physiological pH, in water, which could hydrate the intermediate (but doesn’t). Nope – instead, this charged molecule sits around waiting for a PABA – or a sulfa drug – to bind to it. When PABA binds, the complex exits...

Read More
Exploring Rational Drug Design
Feb17

Exploring Rational Drug Design

Medicinal chemists strive to optimize molecules that fit snugly into their proposed targets. But in the quest for potency, we often overlook the local physics that govern drugs’ binding to these receptors. What if we could rationally predict which drugs bind well to their targets? A new review, currently out on J. Med. Chem. ASAP, lays out all the computational backing behind this venture. Three computational chemists (David Huggins, Woody Sherman, and Bruce Tidor) break down five binding events from the point-of-view of the drug target: Shape Complementarity, Electrostatics, Protein Flexibility, Explicit Water Displacement, and Allosteric Modulation….whew! Note: Before we dive into this article, let’s clarify a few terms computational drug-hunters use that bench chemists think of differently: ‘decoy’ – a test receptor used to perform virtual screens; ‘ligand’ – the drug docking into the protein; ‘affinity / selectivity’ – a balance of characteristics, or how tightly something binds vs. which proteins it binds to; ‘allosteric’ – binding of a drug molecule to a different site on an enzyme than the normal active site. Regular readers and fans of compu-centric chem blogs such as The Curious Wavefunction and Practical Fragments will feel right at home! We’ll start at the top. Shape complementarity modeling uses small differences in a binding pocket, such as a methylene spacer in a residue (say, from a Val to Ile swap) to dial-in tighter binding between a target and its decoy. The authors point out that selectivity can often be enhanced by considering a drug that’s literally too big to fit into a related enzymatic cavity. They provide several other examples with a ROCK-1 or MAP kinase flavor, and consider software packages designed to dock drugs into the “biologically active” conformation of the protein. Electrostatic considerations use polar surface maps, the “reds” and “blues” of a receptor’s electronic distribution, to show how molecular contacts can help binding to overcome the desolvation penalty (the energy cost involved in moving water out and the drug molecule in). An extension of this basic tactic, charge optimization screening, can be used to test whole panels of drugs against dummy receptors to determine how mutations might influence drug binding. Because target proteins move and shift constantly, protein flexibility, the ability of the protein to adapt to a binding event, is another factor worth considering. The authors point out that many kinases possess a “DFG loop” region that can shift and move to reveal a deeper binding cavity in the kinase, which can help when designing binders (for a collection of several receptors with notoriously shifty binding pockets – sialidase, MMPs, cholinesterase – see p. 534 of Teague’s NRDD review). But these...

Read More

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...

Read More
HCV Followup: Anadys Acquired for Active Antiviral
Oct24

HCV Followup: Anadys Acquired for Active Antiviral

It’s been a busy six months for new Hepatitis C (HCV) meds: first, Merck and Vertex have their drugs approved in May, and then Pharmasset leaks PSI-7977 clinical data. Now, Anadys Pharmaceuticals has just announced Phase IIb results for its clinical candidate setrobuvir (ANA-598). The pill lowered virus levels to undetectable limits in 78% of patients after 12 weeks of combination treatment with either ribavirin or pegylated interferon. Anadys notes only one major side effect, a rash occurring in 1/3 of the ‘598-treated patients. The therapy targets patients in tough-to-treat HCV genotype 1 (gen1), unlike PSI-7977, which targets gen2 and gen3. The data seems to have convinced Roche, which acquired Anadys last Monday in all-cash deal analysts say represented a 260% premium over Anadys’s Friday stock closing price. Roche, no stranger to the HCV battle, hopes to integrate setrobuvir into a potential oral drug cocktail with its current suite of polymerase and protease inhibitors. Setrobuvir interacts with N5SB polymerase at the allosteric “palm” binding site, located in the center of the baseball-mitt shaped enzyme. The drug’s sulfur-nitrogen heterocycle – a benzothiadiazine – is the key to virus inhibition; Anadys has installed the motif in all their HCV inhibitors, going back to their 2005 patents. Chemists have known about the virus-targeting properties of this heterocycle for a while, but most derivatives have been culled in pre-clinical testing (see J. Antimicrob. Chemoth. 2004, 54, 14-16 for a brief review). Interestingly, chemists initially prepared benzodiathiazines, such as those in Merck’s chlorothiazide (c. 1957, according to the Merck Index), as diuretics, which found use in diabetic treatment. Over the next 40 years, modified medicines treated conditions ranging from epilepsy and cognitive therapy to hypertension and transcriptase regulation. Tweaked benzodiathiazines first showed anti-HIV and anti-CMV activity in the mid-1990s. One final advantageous wrinkle in this structure: unlike PSI-7977, setrobuvir is not nucleoside-derived. This feature changes its binding behavior, pharmacokinetics, and even its intellectual property strategies, since many current antiviral therapies mimic the nucleosides found in RNA and DNA chains....

Read More