Category → Oncology
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.)
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 American
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.
Since 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.
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.
Novartis’s Afinitor helps Pfizer’s Aromasin to Delay Breast Cancer
Looks like Afinitor (everolimus), a drug marketed by Novartis for various cancers, may soon have a new indication.
Already approved for a variety of diseases – kidney cancer, pancreatic tumors, and organ rejection prevention – Afinitor shows new promise for breast cancer patients. Clinical data released Monday demonstrate marked improvement for hormone-resistant breast cancer patients when Afinitor, an mTOR inhibitor, is used in combination with the aromatase inhibitor Aromasin (exemestane). Patients receiving both drugs delayed disease progression an average of 7 months, versus 3 months for Aromasin alone.
Standard therapy for breast cancer includes treatment with estrogen receptor antagonists, such as Aromasin and tamoxifen, which bind in the estrogen receptor pocket of cancer cells, slowing proliferation (see the excellent NCI website for more information on breast cancer treatment). Aromasin itself has a very similar structure to estrone (a natural body hormone that binds to estrogen receptors) except that it irreversibly modifies the receptor pocket upon binding, making Aromasin a so-called “covalent” or “suicide” inhibitor (see Lila Guterman’s article from Sept. 5, 2011 issue of C&EN for more on drugs that bind for keeps).
Like Aromasin, Afinitor follows the trend of being structurally related to a natural binder of a key cancer target protein. mTOR (mammalian target of rapamycin), the protein target of Afinitor and related macrolides, was first discovered through binding studies using rapamycin, a polyketide natural product found in a soil bacterium from Easter Island (its Polynesian name is Rapa Nui, hence, rapamycin). Rapamycin also goes by the generic name sirolimus, of which so many analogues have been prepared that all go by the catch-all “limus drugs.” The attachment of a hydroxyethyl (CH2CH2OH) tail to rapamycin produces everolimus, which compared to sirolimus demonstrates better pharmacokinetic properties, including higher bioavailability (greater proportion of drug reaching target sites) and a shorter plasma half-life (meaning the drug doesn’t stick around as long, which can help curb toxicity or other side effects).
Note: Please see Sally Church’s post on Pharma Strategy Blog for more info on mTOR pathway biology and coverage of ECCO 2011 conference information regarding everolimus.
Pfizer Scores FDA Nod for Lung Cancer Drug Crizotinib (Xalkori)
FDA has given the regulatory nod to crizotinib, Pfizer’s ALK inhibitor that has proven very effective in the small portion of the population whose lung cancer is driven by the protein.
Pfizer says the drug, to be sold under the brand name Xalkori, will cost $9,600 per month, and it will provide assistance so that patient co-pays will not exceed $100. It’s the first in a handful of new drugs Pfizer is counting on to help offset the sales drain when the patent expires this fall on its blockbuster cholesterol drug Lipitor.
The approval is notable as the second drug/diagnostic combo to get the FDA green light in recent weeks—Plexxikon/Roche’s melanoma treatment Zelboraf is the other.
Also notable? We call the compound an ALK-inhibitor, but scientists didn’t start out looking for an ALK-inhibitor. Work on crizotinib originated at Sugen, a South San Francisco-based biotech first bought by Pharmacia, which was later acquired by Pfizer. Sugen chemists were intent on finding a molecule that blocked c-Met, a protein implicated in tumor metastasis. They had already struck upon a promising amino pyridine scaffold by the time their activities were moved into Pfizer’s La Jolla site, where lead optimization took place.
An optimized molecule, billed as a c-Met inhibitor, was put into clinical trials. Then, as we wrote last year, scientific discovery and serendipity converged to change the course of the drug’s development:
Researchers led by Hiroyuki Mano, a professor of functional genomics at Japan’s Jichi Medical University, found that when a certain chromosome inverted, a fusion occurred in lung cancer cells between the echinoderm microtubule-associated proteinlike 4 (EML4) gene and the ALK gene. The researchers found that the fusion caused tumor formation in mice. A subsequent test determined that about 7% of lung cancer patients had this fusion gene. In a paper published in Nature, the researchers concluded that ALK would make a good drug target (Nature 2007, 448, 561).
As it happened, Pfizer had just learned it had an ALK inhibitor on its hands. The company and Massachusetts General Hospital had evaluated results from large biochemical and cell-based screens to see whether crizotinib was hitting targets other than c-Met, says James Christensen, director of translational research in Pfizer’s oncology unit. Upon characterizing the hits, the collaborators found that it was blocking ALK’s activity.
Better, crizotinib was just as good at blocking ALK as it was at shutting down c-Met. Pfizer scientists believe the dual activity is due to a similarity in a residue on each protein. Specifically, both c-Met and ALK have a particular tyrosine within one of the three phosphorylation sites, called the activation loop, which seems to be responsible for the compound’s activity.
All in all, pretty cool science that has translated into a very promising treatment for some lung cancer patients.
The Right Kinase, Part II – Roche and Daiichi’s Vemurafenib Approved
Last week, the FDA approved Zelboraf (vemurafenib), co-marketed by Roche and Daiichi Sankyo, for the treatment of melanoma characterized by genetic mutation BRAF V600E, which occurs in a subset of the overall patient population. Treatment of late-stage melanoma patients with Zelboraf increases their survival around five months longer than traditional chemotherapy. Cancer-stricken families believe this extra time justifies the $9400 / month price tag for the treatment, considering the dearth of treatments currently available for these near-terminal patients (for a more detailed look into the people who brought vemurafenib to market, read Amy Harmon’s New York Times article series from 2010).
Vemurafenib went from concept to approval in just six years, lightning-fast for pharma, which usually takes decades to bring a drug to market. So, what’s the secret behind its success?
Vemurafenib, developed initially by San Francisco pharma company Plexxikon (acquired in 2011 by Daiichi Sankyo) shows all the hallmarks of rational drug design. Initial screening of a 20,000-member compound library against the ATP-binding site of 3 kinases (Pim-1, CSK, and p38) yielded a 7-azaindole lead structure. This approach, known as fragment-based lead discovery (FBLD) – the concept that a drug can be built up from a tiny piece as opposed to a high-potency binder – may represent a first for the industry, as pointed out by Dan Erlanson of blog Practical Fragments. Further synthetic modification of this azaindole fragment, supported by computer binding studies, showed that a hydrophobic (nonpolar) pocket on the enzyme surface could best be filled by a difluoro-phenylsulfonamide group. Biochemical assays confirmed that a ketone linker (in place of the 3-aminophenyl group shown above) between the azaindole and the sulfonamide increased potency. Additionally, a 5-chloro residue on the azaindole eventually became a 4-chlorophenyl group; it’s unclear how this relatively non-polar group helps improve binding, since early active-site models suggest it faces out towards the watery cell cytoplasm.
How is Zelboraf halting melanoma growth? It all comes down to kinase inhibition, a topic covered with both a story and a Haystack post here at C&EN last year. B-RAF, a common gene overexpressed in melanoma cells, produces a protein kinase that is selectively inhibited by Zelboraf. Once shut off, this pathway reinstates a “lost” negative feedback loop for the BRAF V600E tumor cells, resulting in a cascade failure of growth factors further down the line. Cell growth arrest or apoptosis (cell death) follows, but only for the targeted melanoma cells, with no effect on non-cancerous cells.
In an interesting twist, a review published in July shows that inhibitors of Raf kinases (the family of kinases that includes
the product of the B-RAF gene) can be developed for either the “activated” or “resting” forms of the enzyme. These two forms of the same enzymatic target show remarkably different clinical applications: Zelboraf targets the “activated” Raf kinase. Bayer’s Nexavar (sorafenib), a “resting”-form Raf inhibitor, was approved in 2005 for treatment of kidney and liver cancer, but shows little activity against BRAF V600E melanoma.
Update (4:30PM, 8/25/11) – Deleted “in silico” from screening description. Assays were run in vitro using AlphaScreen beads (PerkinElmer).
Sweet Science: Glucose Regulates Stem Cells, Cancer
Most people think of glucose, a humble sugar, as the fuel for several critical body functions, including muscle contraction, brain function, and a host of cellular processes. As it turns out, glucose function might also make a prime target for the development of regenerative medicine and cancer treatments.
Researchers at the Mayo Clinic led by Dr. Andre Terzic report in Cell Metabolism that glucose plays a pivotal role in “re-induction” of pluripotent stem cells (iPSC) from cells called fibroblasts. These rapidly dividing cells, which normally build connective tissues like collagen, can be convinced to shutter their oxidative, mitochondria-based metabolism in favor of a glycolytic pathway, essentially changing the cells to iPSCs in the process.
Terzic et al, Cell Metabolism 2011
In other glycemic news, Stanford Medical School researchers, led by Dr. Amato J. Giaccia, have reported a small molecule capable of inducing “synthetic lethality” in renal cell carcinomas, a common type of kidney cancer. Treatment of cancer by chemical synthetic lethality combines small-molecule inhibition and genetic mutation to selectively kill cancer cells dependent on these pathways. Carmen briefly covered this advance in the August 8 issue of C&EN.
Two transporters for glucose, GLUT1 and GLUT2, control how kidney cells use sugar; however, genetic mutations cause cancerous cells to favor GLUT1. STF-31, a sulfonamide which targets GLUT1, selectively shuts down glucose transport to those cancerous cells lacking functional VHL tumor suppressor genes, a common mutation in renal cell carcinomas. But tumor cells are notoriously tricky. The Stanford scientists wondered if in the absence of the GLUT1 activity, cancer cells: might simply use an alternative pathway called oxidative phosphorylation to stay alive. They found that adding excess pyruvate (fuel for the oxidative phosphorylation engine) could not compensate for glucose starvation, and RCC cells still died. Other non-specific glucose transporter inhibitors (fasentin or phloretin, which hit GLUT1 and GLUT2 indiscriminately) killed normal kidney cells as well as cancerous cells, which confirms overexpressed GLUT1 as STF-31’s RCC target.
Is Vernalis’ Hsp90 Destined to Be a Blockbuster?
Vernalis shares shot up today after Novartis gave a shout out to AUY922, which blocks a molecular chaperone called Hsp90, in a discussion of its second-quarter results. The Swiss pharma major identified AUY922 in a list of potential blockbusters, a distinction that may seem ambitious to those who have been watching compound after compound targeting Hsp90, which helps stabilize stressed-out proteins, crash and burn.
So what makes the Vernalis drug so interesting? We took a look at the field back in 2007, and at the time it was clear the Vernalis compound differed from most of the other drugs in or poised to enter clinical studies. The first and second-generation Hsp90 inhibitors were all based on geldanamycin, an antibiotic found in soil microorganisms. On its own, the natural product is a poor drug candidate—a quinine moiety renders it highly reactive and highly insoluble. Much of the early discovery work was focused on engineering out those issues, leading to drug candidates from Kosan Bioscience (bought by Bristol-Myers Squibb in 2008, work on the Hsp90 drug, however, seems dead in the water), Conforma Therapeutics (bought by Biogen Idec in 2006, after which the Hsp90 compound was put on the backburner), and Infinity Pharmaceuticals.
But, as we wrote, Vernalis sidestepped geldanamycin altogether:
Vernalis deployed fragment-based drug discovery technology to find low-molecular-weight compounds with a weak binding affinity for Hsp90. Guided by X-ray crystal structures of prospective compounds bound to Hsp90, company researchers optimized the compounds into leads. The end result is a range of drugs that do not all fall under the geldanamycin umbrella.
That’s the structure piece, but another piece of the puzzle is that researchers appear to be figuring out how best to use these compounds. On their own, Hsp90 inhibitors have shown limited to no therapeutic benefit. “It is abundantly clear that with rare exceptions we did not see a lot of single agent activity” with Hsp90 inhibitors, Julian Adams, president of R&D at Infinity, told me last month at the ASCO annual meeting. The lack of activity might have been predicted, he adds, given that it was known that blocking Hsp90 only activated another protein-folding chaperone called Hsp70.
Indeed, evidence is emerging that Hsp90 inhibitors could find use in combinations with other targeted agents and for specific patient populations. Infinity did a deep dive into the data gathered from a Phase I trial combining Infinity’s lead Hsp90 inhibitor retaspimycin and Taxotere in lung cancer patients. The result: signs of strong activity in people with the ALK mutation (the target of Pfizer’s lung cancer drug crizotinib), in heavy smokers, and in people who carried the normal KRas gene.
There is also interest in combining Hsp90 inhibitors with Jak2 inhibitors, like ruxolitinib, conveniently being developed by Novartis and Incyte to treat rare blood disorders. Last fall, Memorial Sloan Kettering scientists showed that Jak2 is a very unstable protein, and blocking Hsp90, which ostensibly helps keep Jak2 pieced together, in combination could improve therapeutic outcomes.
Novartis is recruiting for a slew of clinical trials looking at the effect of combining AUY922 with other targeted agents. It’s early days for AUY922, which is still in Phase II trials. If all goes well, Novartis expects to file for regulatory approval for the compound in 2015.
So will an Hsp90 inhibitor finally make it to market? Detractors? Supporters? Speak up in the comments!