COVER STORY
DRUG CANDIDATES DEBUT POTENTIAL TREATMENTS for cancer, respiratory and heart disease unveiled at ACS meeting CARMEN DRAHL, C&EN WASHINGTON
TAKE A CONFERENCE center ballroom, a crowd of chemists, and drug structures emerg-
ecule that’s well tolerated in animals and carefully scheduling doses of the drug in humans, it could be possible to minimize side effects, he says. The BMS team relied on Notch signaling assays in leukemia and breast cancer cell lines to find leads. They soon learned that for their molecules to work, three chiral centers had to be in the S,R,S configuration. After that, they strove to make the molecules last in the bloodstream. They removed an isobutyl group and tweaked some other parts of their candidate’s succinamide side chain. It was tough to retain
ing from the shroud of secrecy, and you have the recipe for one of the most consistently popular sessions at the ACS national meeting. At the spring meeting in New Orleans, the Division of Medicinal Chemistry’s traditional “First-Time Disclosures” session revealed five drug candidate structures, each from a different company. The molecules face a tough road ahead in clinical trials, but they have at least a chance of becoming medications in the future. Researchers filled the ballroom, furiously scribbling structures on notepads. The session was organized by Albert J. Robichaud, chief scientific officer of Cambridge, Mass.based Sage Therapeutics. The talks have always featured excellent work from companies both large and small, Robichaud told C&EN. But the changes to pharma’s landscape over the past five years have translated into more small firms taking the podium. “I think this is a great example of scientists finding opportunities in small organizations after the significant downsizing of large pharma research groups,” he said. Moreover, he added, the shift adds to the ranks of firms doing high-quality science for the benefit of patients.
CH3
CATHERINE STROUD PHOTOGRAPHY
N
BMS-906024, NOTCH SIGNALING INHIBITOR For some disease targets, an indirect approach may be best. Or so Ashvinikumar V. Gavai and his colleagues at Bristol-Myers Squibb found in their quest toward a potential cancer drug. Gavai unveiled BMS906024, which is an experimental—and slightly roundabout—treatment for a number of cancers, including breast, lung, and colon cancers, and leukemia. Cancers have a tendency to relapse or to become resistant to treatments that once worked. Research at BMS and elsewhere had suggested that a family of proteins called Notch is implicated in that resistance and in cancer progression more generally. Gavai, director of oncology chemistry at BMS in Princeton, N.J., and his team set out to block Notch family signaling. Notch family members lack enzymatic activity, so blocking them directly is difficult. Instead, BMS developed inhibitors of an enzyme that is essential for activating Notch signaling—γ-secretase. Interfering with Notch, even in this indirect way, can have detrimental effects on the gastrointestinal tract. Only two of the four Notch family members are linked to that side effect, Gavai says. But
(From left, front row) Gavai, Weifeng Shan, (second row) Aaron Balog, Patrice Gill, Gregory Vite, (third row) Francis Lee, Claude Quesnelle, (rear row) Wen-Ching Han, Richard Westhouse.
he and his team think their drug will be most effective if it acts on all four family members roughly equally—a so-called pan-Notch inhibitor. By selecting a molCEN.ACS.ORG
13
APRIL 22, 2013
N
CF3
O O
NH2
N H
O CF3
BMS-906024 Company: Bristol-Myers Squibb Target: pan-Notch Disease: breast, lung, colon cancer; leukemia
both a long half-life and activity against Notch, Gavai told C&EN. “You’d optimize one and lose the other.” His team threaded the needle with BMS-906024. Their studies with mice suggest that a dose of 4–6 mg once a week could be effective in people. That’s lower than doses being tested for other Notchtargeted agents, according to the website clinicaltrials.gov. The mouse studies also back the idea that Notch is involved in cancer drug resistance and suggest that Notch could be a target for taking on cancer stem cells, which are notoriously resistant to chemotherapy. BMS-906024 is in Phase I clinical trials, both alone and in combination with other agents. Patients with colon, lung, breast, and other cancers are receiving intravenous doses of the compound to determine its safety and optimum dose ranges.
LGX818, MADE TO FIGHT MELANOMA Targeted drugs such as Gleevec have changed the face of cancer therapy. But cancer has a way of developing resistance to even these customized treatments, which are designed to block kinase enzymes gone awry. At the meeting, Novartis chemistry group leader John Tellew talked about LGX818, a drug candidate taking aim at resistant melanoma. Roughly 50% of all melanoma patients have tumors with a mutation to a kinase called BRAF, which normally transmits cell growth signals. The most common BRAF mutation, which replaces a valine amino acid with a glutamic acid, also occurs in some colon and thyroid tumors. This abnormal BRAF turns the signaling pathway on in an unregulated fashion. A drug on the market called vemurafenib targets this V600E mutation specifically. But while patients initially respond to this drug, nearly all develop resistance and relapse in mice at tolerated doses, so it was back to within months. the drawing board. To face this challenge it took two teams With abbreviated efficacy and tolerat the Novartis Institutes for Biomedical ability studies in mice, designed to speed Research—Tellew’s, in San Diego, and Danthroughput, they evaluated many comiel J. Poon’s, based in Emeryville, Calif. The pounds until they found better options, groups had regular videoconference meetsuch as sulfonamides. Their drug candiings and shipped samples date, LGX818, emerged to each other, up and after extensive tweaks to a O O down the California coast, sulfonamide. It binds not S Tellew told C&EN. to the active form of the H3C NH It’s possible to block kinase but to an inactive F BRAF with molecules form—much like vemuthat bind to any of sevrafenib. Compared with N Cl eral forms of the kinase, vemurafenib, however, N including the active form LGX818 was superior at and two inactive conforkilling mutant BRAF tuN N O mations. The Novartis mor cells. HN team began by targeting In rat and mouse toxiN OCH3 H the active form. Phenol cology studies, LGX818 and oxime motifs are comperformed well. The comLGX818 mon in these types of inpound also shrank grafted Company: Novartis hibitors, but they can lead human tumors bearing the Institutes for Biomedical to compounds with too V600E BRAF mutation in Research poor pharmacokinetics to rats and mice. Target: V600E BRAF be useful. LGX818 is currently kinase Working with a triin Phase Ib/II clinical triDisease: melanoma arylimidazole skeleton, als. Patients with colon the team found that cancer or melanoma with 2-amino-3-methoxypyridine was a decent the BRAF mutation, including patients replacement for the phenol or oxime. Alresistant to other BRAF-targeted drugs, are though the resulting compounds passed receiving LGX818 pills alone or as part of biochemical tests for selectivity and drugdrug cocktails to determine whether the like properties, they didn’t shrink tumors drug is safe and efficacious. CEN.ACS.ORG
14
APRIL 22, 2013
▲ (From left) Qiong Zhang,
Tim Machajewski, William Antonios-McCrea, Zilin Huang, Cynthia Shafer, Poon, Abran Costales, Martin Sendzik, Jeff Jin, Aaron Smith. ◀ (From left) Xia Wang, Tellew, Shifeng Pan, Yongqin Wan, Shenlin Huang, Zuosheng Liu.
Not pictured: William Wang, Yongping Xie, Ann Marie Madera, Maureen McKenna, Sabina Pecchi, Paul Renhowe, Anu Sharma.
AZD5423, FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE Collaborations between large pharmaceutical companies usually don’t happen until relatively late in drug development. But the challenge of developing a new drug for respiratory diseases prompted AstraZeneca to collaborate from the get-go. In New Orleans, Thomas Hansson, a senior principal investigator at the company, presented the fruit of international teamwork with Bayer Schering Pharma—AZD5423, a potential medication for chronic obstructive pulmonary disease (COPD). Inflammation is a major cause of the airway blockages people experience in asthma or COPD. Inhalable glucocorticoids, a class of steroid hormones, can decrease that inflammation and swelling, either alone or in combination with agents that dilate the respiratory tract. The most common cause of COPD is smoking, so quitting can bring relief in some cases. Many people with COPD don’t respond to steroids. And long-term steroid use can lead to side effects including increased risk of infections. So Hansson and his colleagues aimed to develop a safer, more efficacious, nonsteroidal COPD treatment. They targeted the receptor to which
COURTESY OF NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH (BOTH)
COVER STORY
BIRINAPANT, APOPTOSIS INHIBITOR
(From left) Guangyao Yu, Yijun Deng, Gurpreet Singh Kapoor, Condon, Susan Rippin, Martin Graham, Angeline Mufalli, Jennifer Burns, Martin Seipel, Eric Neiman, Thomas Haimowitz, Christopher Benetatos, Yasuhiro Mitsuuchi, Srinivas Chunduru. Not pictured: Divya Goel
COURTESY OF TETRALOGIC PHARMACEUTICALS
It’s often said that two heads are better than one. For Malvern, Pa.-based TetraLogic Pharmaceuticals, it was combining two copies of a molecule into one drug candidate that did the trick. Stephen M. Condon, vice president for chemistry at TetraLogic, told the story of that candidate, birinapant, in New Orleans.
Birinapant was designed to reinstate cancer cells’ ability to die. Many cancers that are resistant to conventional chemotherapy drugs have defects in the cell death pathway known as apoptosis. The human body uses apoptosis every day to clear away abnormal or unwanted cells. Apoptosis is a tightly regulated process, Condon explains, with a network of proteins that activate or block the process. TetraLogic’s target is a family of proteins
CEN.ACS.ORG
15
APRIL 22, 2013
CATHARINA FYRBERG
glucocorticoids bind. When O activated, this receptor O helps to regulate a variety F3C N N H of genes, including some N linked to inflammation. Work from many teams OCH3 had already turned up nonsteroidal molecules that AZD5423 F acted on the glucocorticoid AZD5423 receptor. Hansson’s team Company: AstraZeneca at AstraZeneca entered Target: glucocorticoid receptor into a four-year collaboraDisease: chronic obstructive tion with researchers at pulmonary disease Bayer Schering Pharma, in Germany, to identify (From left) Tomas leads of their own with high-throughput anti-inflammatory Klingstedt, Göran screens. It’s difficult to obtain nonsteroiactivity anymore,” Carlström, Anders dal compounds potent enough to be used he says. Eriksson, Karl in a dry-powder inhaler, so that was one The collaboraEdman, Matti of the team’s biggest challenges, Hansson tion with Bayer’s Lepistö, Hansson, Martin Hemmerling. says. team made it easier The team transformed a sulfonamide to solve that cohit from a screen into molecules that acted nundrum. The two on the glucocorticoid receptor efficiently. firms explored multiple chemical avenues The molecules set off red flags in a biologiin parallel. That effort, coupled with cal test for potential carcinogens, however, structural and computational chemistry because they were forming aromatic amine work at AstraZeneca, led to a solution. metabolites that can be toxic to genes. The researchers decided to work with a Hansson’s team was able to remove those completely different class of molecules— motifs, “but then the compounds had no indazole ethers—because this resolved
the carcinogen issue while still controlling glucocorticoid receptor signaling. After multiple rounds of adjustments, the team tested their most potent compounds in lab animals designed to help approximate human lung disease. AZD5423 performed best in those tests, and was selected to enter human clinical trials. The compound is now in a Phase II study in patients with COPD, where its efficacy and safety are being measured against that of a typical steroid or a placebo. “It was a lot of fun to work on this project,” Hansson says. “AstraZeneca and Bayer each brought pieces to the puzzle.”
OH F O H3C
H3C
N H
N H
N H
N H
N O
NH
O
NH N
O F OH
BIRINAPANT Company: TetraLogic Pharmaceuticals Target: Inhibitor of Apoptosis proteins Disease: cancer
called the Inhibitor of Apoptosis proteins. As their name suggests, these proteins block apoptosis. They interfere with protease enzymes that carry out cellular dismantling. TetraLogic’s aim is to lift that blockade to restart apoptosis in tumors. Many tumors have excesses of the apoptosis inhibitor proteins relative to normal cells, so
COVER STORY
targeting this process has the potential to be less toxic to normal cells compared with conventional chemotherapy. It turns out nature has a way of negating the inhibitor proteins’ actions—a protein known as Smac. TetraLogic’s founders demonstrated that only a tiny portion of Smac is necessary to keep the inhibitor proteins at bay—the four amino acids at the protein’s N-terminus. “Once you can get a protein down to a tetrapeptide,” about the size of a small-molecule drug, “you start getting a lot of interest from the pharma community,” Condon told C&EN. Peptides fall apart in the body too quickly to be drugs, so Condon’s team worked with molecular mimics of the Smac tetrapeptide. Their biggest advance was realizing that combining two copies of their tetrapeptide mimics into one molecule made their compounds highly effective at reinstating apoptosis in cancer cell lines. Many proteins in the apoptosis pathway function as dimers, so using these so-called bivalent mimics against them makes sense, Condon said. However, several of the bivalent compounds were associated with pronounced body weight loss in mice. Condon’s team eventually learned that replacing a branched side chain on their peptide mimics and adding a hydroxyl group to a proline residue improved the tolerability for the animals without impacting the antitumor effect. With that, birinapant was born. In mice, birinapant shrank tumors. The compound has been in clinical trials since 2009, both on its own and in combination with other chemotherapy drugs such as irinotecan and gemcitabine. On the basis of other biochemical work on the apoptosis pathway, TetraLogic thinks these drugs could act in synergy with birinapant to treat cancer, Condon said. Birinapant is currently in Phase II clinical trials in patients with acute myeloid leukemia, pancreatic cancer, or ovarian cancer. Although these trials don’t have a control group, the emerging data are promising, TetraLogic chief executive officer John M. Gill told C&EN. (Early-stage cancer clinical trials are commonly run without placebo groups.) The birinapant trials show preliminary evidence both that the drug is having the desired effect and that this effect is associated with signs of clinical activity. Given these results, the company plans to launch randomized Phase II studies early in 2014.
MGL-3196, THYROID HORMONE ANALOG No conversation about preventing heart disease would be complete without mentioning statins, the blockbuster cholesterol-lowering class of medications. Yet not all patients on statins reach the cholesterol-lowering goals their doctors recommend. Statins aren’t very good at managing other lipids linked to heart disease, such as triglycerides. And nearly one in five people taking statins experiences side effects, such as muscle weakness. Some experts see opportunities for new types of cholesterollowering drugs to gain a foothold. That’s the spirit behind MGL-3196, an experimental medication discovered at Hoffmann-La Roche’s now-shuttered site in Nutley, N.J., and currently in development at Fort Washington, Pa.-based Madrigal Pharmaceuticals. Martha J. Kelly, Madrigal’s head of research and compound
development, unveiled the molecule. MGL-3196 has a mode of action distinct from that of statins. Instead of preventing cholesterol synthesis, as statins do, MGL3196 is designed to increase cholesterol uptake into the liver and increase its metabolism, and thereby its elimination from the body through the bile. The compound is also intended to boost fat metabolism, thereby reducing triglyceride levels. Specifically, MGL-3196 is a thyroid hormone analog, designed to target a thyroid hormone receptor in the liver. These receptors regulate genes involved in cholesterol regulation and metabolism. Thyroid hormone affects the body in many ways. Roche’s team sought the hormone’s beneficial metabolic effects while avoiding unwanted effects such as elevated heart rate and bone loss. The side effects tend to arise when activating the alpha form of the thyroid hormone receptor and when activating the receptor in tissues
WHERE ARE THEY NOW?
An Inflammation Drug Flames Out Molecules revealed at the ACS meeting often don’t pan out, despite high hopes. For instance, the road has been rocky for blockers of a kinase enzyme called p38, experimental drugs designed to treat rheumatoid arthritis or Crohn’s disease. At the spring 2002 ACS N national meetO ing, Boehringer Ingelheim debuted the structure of its p38 blocker BIRB 796. But the firm has since pulled the plug on this compound. Both rheumatoid arthritis and Crohn’s involve chronic inflammation. BIRB 796 was designed to mitigate those symptoms, because the kinase p38 had been implicated in triggering inflammation. After the 2002 symposium, BIRB 796 got a new name—doramapimod. The molecule underwent testing in people with Crohn’s
CEN.ACS.ORG
16
disease, rheumatoid arthritis, and psoriasis. In Crohn’s, the trial uncovered “no evidence for clinical efficacy” (Clin. Gastroenterol. Hepatol. 2006, 4, 325). Results in psoriasis and rheumatoid arthritis were similarly disappointing, accord-
doramapimod became a reactive epoxide in the liver, which caused the toxicity issues (J. Appl. Toxicol., DOI: 10.1002/ jat.1622). Several other p38 blockers met a similar end. But while the p38 failures were “a major surprise and unexO O pected,” according N to a 2009 review arN N N ticle (Ann. Rheum. H H Dis., DOI: 10.1136/ ard.2009.119479), Doramapimod (BIRB 796) not all has been ing to Stanford University lost. Researchers are Medical Center’s Mark C. now looking at kinases Genovese, who penned upstream of p38 in inan editorial about the flammation signaling as agent in 2009 (Arthritis potentially more effecRheum., DOI: 10.1002/ tive drug targets. In 2011, art.24264). Boehringer a team in Europe used Ingelheim ultimately doramapimod as a startdropped doramapimod ing point toward developbecause patients on it ing blockers of another were developing liver kinase associated with function abnormalities. A lymphoma (ChemMed2011 study from a JapaChem, DOI: 10.1002/ nese firm concluded that cmdc.201100168).
APRIL 22, 2013
O
H N N Cl
H N
molecule’s “most profound effect.” Taub later cofounded Madrigal, N which acquired the candidate and CN Cl some other VIA assets in 2011. In animal testing, MGL-3196 MGL-3196 lowered levels of cholesterol and Company: Madrigal triglycerides without affecting Pharmaceuticals high-density lipoprotein, or HDL Target: thyroid hormone (good cholesterol), or triggering receptor-β, in the liver side effects in the heart. It also Disease: high cholesterol, high (From left) Kelly, outside the liver. So the Roche team appeared to work in combination Taub, Brian triglycerides sought molecules that were targeted with statins, lowering lipid levels Cunningham, and Edward Chiang. to the liver and were selective for thymore than would be expected by roid hormone receptor-β. the drug candidate that tocombining the molecules’ individual effects. Rather than screening for comday is known as MGL-3196. The molecule has completed Phase I pounds by assessing only their binding But it didn’t get that name right away. In clinical trials. To evaluate its safety and to to the target, Roche’s team used a screen 2008, the molecule moved from Roche to obtain proof of concept of its effects on that also assessed compounds’ activity. San Francisco biotech VIA Pharmaceuticals lipid levels, otherwise healthy volunteers This helped them find molecules early on along with Rebecca A. Taub, who left her with slightly high low-density lipoprotein that were selective for the β-receptor. To position of vice president and head of meta(LDL) levels received various daily doses replace the electron-rich phenols common bolic disease research at Roche to become of the drug candidate or a placebo. In the on previous compounds, the chemists VIA’s senior vice president for research and two-week multiple-dose study, the drug apchose pyridazinones. (Phenols can confer development. Roche scientists at the time peared safe at all doses tested. Those receivpoor metabolic properties.) Along the way, were focused not on cholesterol but on othing MGL-3196 had statistically significant they noted the molecules reached the liver er metabolic disease areas, Taub told C&EN. reductions in LDL levels, and some statistiselectively and had poor penetration into The move made it possible to test the lipidcal trends from the study suggest reductions the heart and other tissues. All this led to lowering activity, which Taub called the in triglycerides as well. ◾ O
COURTESY OF MADRIGAL PHARMACEUTICALS
O N
The
O
uture is here.
The pHit Handheld Scanner. The world’s frst calibration-free, non-glass, dry-storage pH meter. Learn more and order now at SenovaSystems.com.
CEN.ACS.ORG
17
APRIL 22, 2013
