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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!

Selectivity Strategies

Selectivity Strategies for Rational Design | Credit: Huggins, Sherman, Tidor; J. Med. Chem.

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

Affinity Optimization

Affinity Optimization - Black dot represents the optimal minimum energy between Coulombic forces (green) and desolvation penalty (blue) | Credit: Huggins, Sherman, Tidor; J. Med. Chem.

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 shifting proteins also swim in a sea of water and other cytoplasmic goodies. This means that drug designers, whether they like it or not, must account for explicit water molecules. The authors even suggest a sort of “on-off” switch for including the bound water molecules, but contend that more efforts should be directed to accurate modeling of water in these protein settings.

Finally, the authors weigh the effects of allosteric binding, the potential for a modeled molecule to be highly selective for a site apart from where the protein binds its native ligand. The authors consider the case of a PTP1B ligand that binds 20Å away from the normal active site, at the previously mentioned “DFG loop.” Since this binding hadn’t been seen for related phosphatases, it could then be used to control selectivity for PTP1B.

In each section, the authors provide examples of modeling studies that led to the design of a molecule. Two target classes recur oftenCOX and HIV inhibitors throughout the review: HIV protease inhibitors (saquinavir, lopinavir, darunavir) and COX-2 inhibitors (celecoxib), which have all been extensively modeled.

Two higher-level modeling problems are also introduced: the substrate-envelope hypothesis, which deals with rapidly mutating targets, and tailoring molecules to take rides in and out of the cell using influx and efflux pumps in the membrane. Since different cell types overexpress certain receptors, we can use this feature to our advantage. This strategy has been especially successful in the development of several cancer and CNS drugs.

Overall, the review feels quite thorough, though I suspect regular Haystack readers may experience the same learning curve I did when adapting to the field-specific language that permeates each section. Since pictures are worth a thousand words, I found that glancing through the docking graphics that accompany each section helped me gain a crucial foothold into the text.

Celgene & Avila Forge Permanent Ties

Today brought a spate of M&A activity in the biotech space, with Amgen unveiling a $1.2 billion bid for Micromet, and Celgene agreeing to pay up to $925 million for Avila Therapeutics. Both deals brought the acquirer a drug in development to treat blood cancers, while also adding a platform technology to their research engines.

Being all about the chemistry, The Haystack is particularly interested in the Celgene/Avila deal, which involves covalent drug development technology. Celgene is paying $350 million upfront, with the promise of up to $195 million more if Avila’s lead covalent drug candidate, AVL-292, reaches the market. Pushing other covalent drugs through the pipeline could garner Avila shareholders another $380 million.

So what is a covalent drug, anyway? As C&EN’s Lila Guterman described last fall, covalent drugs form a permanent link with their target. By comparison, most conventional drugs are designed to reversibly bind to their targets—in other words, they can stick and “un-stick” to a protein.

The beauty of a covalent drug is that its specificity and potency means it can be given in low doses. As Guterman explains, patients only be given enough of the drug for molecule to reach each target protein molecule, and then another dose only when the body has generated more of that target protein. The low dose means less potential for drug-drug interactions and off-target effects.

Indeed, for years, scientists avoided developing covalent drugs out of fear that serious toxicity will arise if a covalent drug happens to permanently stick itself to the wrong protein. Check out Guterman’s piece for a cautionary toxicity tale from none other than “Rule-of-Five” inventor (and former Pfizer researcher) Christopher Lipinski.

The current generation of covalent drugs, however, is designed to assuage those fears through their highly selective and weakly reactive nature. Avila isn’t the only one banking on better molecular design leading to successful drugs: Zafgen’s obesity drug candidate ZGN433 also covalently binds to its target, an approach that—if it works—could enable it to sidestep the side effect issues that have plagued the obesity drug space.

So are these covalent drugs worth the price tag? Avila’s pipeline is relatively young, meaning there isn’t a lot of data to go on: AVL-292 is in Phase I studies in lymphomas; a compound targeting mutant EGFR is also in Phase I trials; meanwhile, two Hepatitis C drug candidates in preclinical studies. The company has also made public preclinical date on its PI3Kα-selective inhibitor (the same target as Intellikine’s INK1117, one of the drivers behind Takeda’s $190 million acquisition of Intellikine.).

How Jagabandhu Das made dasatinib possible

In my story on how drugs get their generic names for this week’s issue of C&EN, I briefly discussed how the chronic myelogenous leukemia medication Sprycel (dasatinib), mentioned in this Haystack post by SeeArrOh, ended up being named after Bristol-Myers Squibb research fellow Jagabandhu Das. Even though Das, or Jag, as his coworkers call him, didn’t discover the molecule that bears his name, the program leader for Das’s team, Joel Barrish, says dasatinib wouldn’t have existed without him.

So how’d Das make a difference? About one and a half years into the search for a kinase inhibitor that might be able to treat chronic myelogenous leukemia, “we were hitting a wall,” Barrish, today vice-president of medicinal chemistry at BMS, recalls. “We couldn’t get past a certain level of potency.”

Early on, the team’s work suggested that a 4′-methyl thiazole was critical for potency. Replace the methyl with a hydrogen, and potency went out the window. But Das challenged that dogma, Barrish says. He thought the compound series had evolved to the point where it would be a good idea to go back and test those early assumptions. His hunch paid off– in the new, later kinase inhibitor series, it turned out that removing the methyl group from the thiazole actually boosted potency. Thanks in large part to that discovery, the team eventually was able to make kinase inhibitors with ten thousand fold higher activity.

Dasatinib (J. Med.Chem.)

“Jag didn’t stop there,” Barrish says. After debunking the methyl dogma, Das found a way to replace an undesirable urea moiety in the team’s inhibitors with a pyrimidine group, which improved the inhibitors’ physical properties. With help from Das’s two insights combined, eventually BMS’s team came up with the molecule that became dasatinib (J. Med. Chem., DOI: 10.1021/jm060727j).

Generic naming requirements are extensive, but the committees involved in the naming process are willing to use inventors’ names as long as they fit the criteria.
But sometimes, Barrish says, “there’s luck involved in who makes the final compound.” In the dasatinib story, though, it was clear that Das’s discoveries were the keys to success.

When dasatinib was in clinical trials and it came time to put forward a set of possible generic names for consideration, Barrish didn’t have to think too hard about who was most responsible for his team’s success. “It was very clear in my mind that it was Jag,” he says. So he added dasatinib to the list.

“I admit, it was one of those things you do and you kind of forget about it, thinking, ‘oh, they’ll pick something else’,” Barrish says. When dasatinib ended up being the name of choice, he says, it made the entire team feel good. “And obviously, Jag was quite pleased with it.”

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 Science wrap-up at years’ end. Derek also left us with a tantalizing tidbit for 2012 – the long-awaited “Things I Won’t Work With” book may finally be coming out!

5. Active Antibacterial Development – In the middle of 2011, several high-profile and deadly bacterial infections (Germany, Colorado, among others) shined a spotlight on those companies developing novel antibacterials. We explored front -line antibiotics for nasty Gram-negative E.coli, saw FDA approval for Optimer’s new drug Fidiclir (fidaxomicin) show promise against C. difficile  and watched Anacor’s boron-based therapeutics advance into clinical testing for acne, and a multi-year BARDA grant awarded to GSK and Anacor to develop antibacterials against bioterrorism microorganisms like Y. pestis.

6. Obesity, Diabetes, and IBS – Drugs for metabolic disorders have been well-represented in Haystack coverage since 2010. Both Carmen and See Arr Oh explored the vagaries of Zafgen’s ZGN-433 structure, as the Contrave failure threatened to sink obesity drug development around the industry. Diabetes drugs tackled some novel mechanisms and moved a lot of therapies forward, such as Pfizer’s SGLT2 inhibitors, and Takeda’s pancreatic GPCR agonist. Ironwood and Forest, meanwhile, scored an NDA for their macrocyclic peptide drug, linaclotide.

7. The Medicine Show: Pharma’s Creativity Conundrum – In this piece from October, after Steve Jobs’ passing, Forbes columnist Matt Herper both eulogizes Jobs and confronts a real ideological break between computer designers and drug developers. His emphasis? In biology and medical fields, “magical thinking” does not always fix situations as it might in computer development.

We hope you’ve enjoyed wading through the dense forest of drug development with Carmen, Aaron, Lisa, and See Arr Oh this past year. We here at The Haystack wish you a prosperous and healthy 2012, and we invite you to come back for more posts in the New Year!

ARIAD Presents PACE Data; Provides Potential Gleevec Backup

Sufferers of chronic myeloid leukemia (CML), a rare and tough-to-treat blood cancer, received some good news at the 2011 Americanponatinib Society of Hematology meeting in San Diego this week. On Monday, ARIAD Pharmaceuticals disclosed new results from the Phase 2 PACE trial of its lead drug ponatinib (AP24534). The data (covered by FierceBiotech, Xconomy, and TheStreet), indicate major responses to the drug in ~40% of recipients, even in advanced or refractory (resistant to treatment) CML .

With these numbers in hand, ARIAD enters a tight race, already populated by headliners like Gleevec (imatinib), which in 2001 made a splash as a first-line CML therapy. Drugs such as Gleevec and ponatinib belong to the family of tyrosine kinase (TK) inhibitors, which dock with a mutated protein called Bcr-Abl. This protein (actually a fusion of two distinct proteins via a chromosomal mishap) triggers disease by accelerating blood cell creation, leading to uncontrolled growth and eventually CML.

imatinibSince cancers constantly evolve, new mutations in the TK active site had rendered Gleevec ineffective for certain variations of CML. Many of the PACE trial patients had previously tried newer TK inhibitors, such as Sprycel (dasatinib, BMS) and Tasigna (nilotinib, Novartis), and found that their CML had become resistant due to a single amino acid mutation in the kinase active site, which swapped a polar residue (threonine) for a carbon chain (isoleucine). So, ARIAD chemists decided to develop a drug that borrowed the best points from the earlier therapies, but capitalized on this mutation (A pertinent review in Nature Chemical Biology covers early examples of “personalized” cancer drugs developed for disease variants).

So, how did they accomplish this particular act of molecular kung-fu?  For that, we hit up the literature and go all the way back to . . . 2010. As explained in a development round-up (J. Med. Chem., 2010, 53, 4701), most approved Bcr-Abl inhibitors share several traits: densely-packed nitrogen heterocycles linked to a toluyl (methyl-phenyl) amide, then a highly polar end group, such as piperazine or imidazole. Since the mutation axed a threonine residue, the hydrogen-bond donor adjacent to the ring in earlier drugs was no longer necessary. So, chemists replaced it with a vinyl group.

A computer analysis designed to achieve better binding and drug-like properties suggested an alkyne linker might fit into the mutated active site even better than a vinyl group, so that’s ultimately what ARIAD installed. The program also suggested moving an exocyclic amino group into the aromatic (forming an uncommon imiadzo-[1,2-b]-pyridazine, green in picture). Borrowing the best stuff from other therapies, ARIAD’s chemists also wove in the “flipped” amide and -CF3 motifs (both blue) from nilotinib, as well as the methylpiperazine (red) from imatinib.Binding overlay

With computational rendering (Cancer Cell, 2009, 16, 401) ARIAD scientists could overlay both imatinib and ponatinib in the mutated enzyme’s active site (see picture, right). Notice that unlike imatinib, ponatinib avoids bumping into isoleucine 315. Ponatinib also gets a little extra binding oomph by poking its CF3 group into a hydrophobic pocket near the bottom of the active site.

Shedding Light on Cancer Cells

Quyen Nguyen is a surgeon at the University of California, San Diego who has worked with chemists to develop molecular beacon type dyes that light up when they come into contact with cancerous tissue or nerve cells. This could give surgeons a sort of chemistry-based augmented reality, showing them exactly where and where not to cut.

Using Gene Expression Patterns to Repurpose Drugs

Late last month, researchers from many different fields gathered at the Computer History Museum in Mountain View, California, to discuss the benefits of open science and data sharing. One of the best talks from that event, the Open Science Summit, was delivered by Joel Dudley, the co-founder of NuMedii, a firm that aims to find new indications for medications.

Dudley has repeatedly found new uses for old drugs by picking through public data sets about the gene expression profiles of different diseases. He then looks for medications that are known to reverse those profiles.

Much of the data that Dudley uses comes from the Gene Expression Omnibus, which he regards as a gold mine.

Life Sciences in the Era of Big Data from Open Science Summit on FORA.tv

A full list of videos from the Open Science Summit is also available.