ANDREW GOOD & JODI MUCKELBAUER/BMS (BOTH)
SCIENCE & TECHNOLOGY
cycle’s synthesis without using DNA. “It’s perceived that macrocycles are tough to make, but we’ve solved all the real challenges so far,” Ensemble’s Chief Scientific Officer Nicholas K. Terrett said at the meeting. With this platform, Ensemble has discovered macrocycles that block the interaction of tumor necrosis factor (TNF) with its receptor, a notoriously tough-to-target interaction that underpins inflammatory diseases such as rheumatoid arthritis. So far, the only marketed drugs that combat this interaction are biologicals that must be injected. Terrett’s coworkers have found an orally active macrocycle called E-32712 that, via the TNF mechanism, is effective at treating rats with arthritic joints. The compound’s structure was not disclosed, but Terrett noted that it has been selected for further preclinical studies.
TIED UP A computer
model (left) of an acyclic compound docked to β-secretase convinced a BMS team to try macrocycles. The X-ray structure of one macrocycle bound to β-secretase is at right.
BIG HOPES RIDE ON BIG RINGS ACS MEETING NEWS: Constraining molecules in macrocyclic
rings could help address challenges in drug discovery CARMEN DRAHL, C&EN WASHINGTON
A 15-MEMBERED RING might seem like
too daunting a molecule to test in a drug discovery program. But in some cases, it might be just what the doctor ordered. At a symposium at last month’s ACS national meeting in Washington, D.C., researchers from industry and academe shared their experiences with macrocyclic rings before the Division of Medicinal Chemistry. “As a tool in the drug discovery field, macrocycles are underutilized,” symposium organizer Paul M. Scola said in a phone interview. A senior principal scientist at Bristol-Myers Squibb (BMS), Scola noted that when applied strategically, a macrocycle—a compound with a ring of 12 or more atoms—may enhance binding affinity, target selectivity, and metabolic stability compared with its open-chain counterpart. Despite often defying Christopher Lipinski’s “Rule of Five,” a series of guidelines for determining whether a molecule is likely to be an orally active drug, macrocycles can possess druglike properties, he added. That problem-solving potential notwithstanding, macrocycles represent just a small fraction of the total population of marketed drugs. Nearly all of those come
from nature, with the antibiotic erythromycin and the immunosuppressant rapamycin as two examples. Because existing macrocyclic drugs are useful against infections, cancer, and other indications, chemists are trying to learn more about when a synthetic macrocycle might be a good choice. They are taking advantage of versatile reactions, such as olefin metathesis and click chemistry, to make more diverse macrocycles than ever before (Nat. Rev. Drug Disc. 2008, 7, 608). Take Ensemble Discovery, a Cambridge, Mass.-based biotech company. There, chemists use DNA to guide the synthesis of thousands of different macrocycles in a single reaction vessel and then test their ability to disrupt biologically relevant interactions between proteins. The technology is built on work carried out in company founder David R. Liu’s lab at Harvard University. If a hit shows promise in initial tests, Ensemble can scale up that macro-
THE POTENTIAL to tune protein-protein
interactions is a big reason why macrocycles are attracting attention, chemical biologist Paramjit S. Arora of New York University commented at the meeting. The vast majority of today’s drugs target enzymes, which usually have well-defined binding pockets. Interactions between proteins are harder to target because of the larger, flatter surface area involved. “You typically can’t make compounds the size of [acetylsalicylic acid] for targeting a protein-protein interaction. That’s why we’re seeing molecules larger than that in this symposium,” Arora said. Arora builds 13-membered rings to stabilize short peptides in α-helical conformations. Helices play key roles in many protein-protein interactions, including some implicated in HIV and cancer. By mimicking helical secondary structure, Arora hopes to build tools for probing protein-protein interactions, and perhaps even new therapeutics, he said at the symposium. To that end, his team recently described a set of computational tools for predicting which protein-protein interac-
“It’s time for macrocycles to become more visible in drug discovery.”
WWW.CEN-ONLINE.ORG
54
SEPTEMBER 7, 2009
NON STOP: IP to INDՓ
Taking you from IP to IND
tions might be good targets for helix mimics (Mol. Biosyst., DOI: 10.1039/b903202a). A portion of each macrocycle Arora uses acts as a surrogate for a hydrogen bond in a nascent helix. That molecular nudge is enough to encourage floppy, unstructured peptides, which ordinarily would never stably remain in a secondary structure, to coil into a helical shape on their own. Stabilized helices are more resistant to degradation by proteases and potentially enter cells more readily than linear peptides. Those RIGHT FIT Most drugs ecule’s selectivity,” target enzymes benefits often hold true when Nelson said at the meeting. with well-defined drugmakers make macrocyclic Varying the macrocycle’s pockets (left). drug candidates containing pepInteractions between size altered its conformation tidic moieties. and led to selective kinase proteins (right) might be engaged by Selectivity can be another of inhibitors, which his team macrocycles.. macrocycles’ perks, as Adam Nelused to clarify the biological son and coworkers at the Univerrole of a particular kinase sity of Leeds, in England, learned. (Chem. Biol. 2009, 16, 15). They modified the structure of a broadMeanwhile, at BMS, making a macrocyspectrum kinase inhibitor, staurosporine, cle helped chemists streamline a drug disto make a family of macrocyclic analogs. covery program’s lead structure while also “We were interested in the relationship of improving binding affinity for its target. the macrocycle’s conformation to the molAt the session, senior research investiga-
INDAZOLES
N N
H2N
Boc
O
B10721
N
N NH
H2N
N NH2
M11197
N
O
M11223
N
N I
H10729
M11198 HO
Boc
B10726
CUSTOM SYNTHESIS UPON REQUEST
Cl N NH
B11187
O N NH
B11188
F Br
F10715
Br
O
F11297
N NH
N NH
O OH
H
F11366
I11369 O
N NH
B11219
N NH
NC
NH
I11298
C10722
N NH
N
I11203
B10733
WWW.CEN-ONLINE.ORG
N
CH3
NH
F
HN
O HN
To make macrocycles, the BMS team relied on a late-stage olefin metathesis reaction. ConstrainTZP-101 ing their candidates in a ring gave a modest 10- to 20-fold enhancement in binding affinity for β-secretase and allowed the researchers to remove portions of the molecule that weren’t critical for activity. Unfortunately, the new candidates couldn’t reach the brain, either. MACROCYCLIZATION often improves
O
H
Cl N NH
N
H10724
ALL COMPOUNDS AVAILABLE NOW
Br
Br
HO
N NH
O
O
O
O
I
O
tor Lawrence R. Marcin described a series of diaminopropanes that blocked the enzyme β-secretase, which is thought to be a desirable target for Alzheimer’s disease. Those molecules never reached clinical trials because they couldn’t penetrate brain tissues efficiently. While the BMS team pondered further adjustments, a molecular model of one compound bound to β-secretase provided a clue as to what to try next. “We saw that two portions of the molecule were intrinsically coming together on binding, and we realized we could tie them together as a macrocycle,” Marcin told C&EN.
56
SEPTEMBER 7, 2009
binding affinity, but it’s important to be careful when interpreting those benefits in thermodynamic terms, organic chemist Stephen F. Martin of the University of Texas, Austin, who did not attend the symposium, told C&EN. The prevailing belief is that preorganizing a molecule lowers the entropic penalty experienced on binding to a protein. But independent work by Martin and Mark R. Spaller of Dartmouth Medical School, in Hanover, N.H., suggests that’s not always true and that other factors may contribute to the boost in binding affinity (Angew. Chem. Int. Ed., 2006, 45, 6830; Biopolymers 2008, 89, 653). “The question of why this happens is something we’re still trying to sort out,” Martin said.
COURTESY OF PARAMJIT ARORA (BOTH)
SCIENCE & TECHNOLOGY
Delays in recuperating gastroTZP-101 is given intravenously, but intestinal function, called postopfurther modifications have led to a varierative ileus, are leading causes of ant that can be taken orally. The strucextended hospital stays, Mark L. ture of that candidate, called TZP-102, Peterson, vice president of intelwas not disclosed. lectual property and operations Both molecules are also being at Tranzyme, said at the session. evaluated as potential treatments for Because signaling by the hormone gastroparesis, a delayed emptying of ghrelin boosts motility in the GI tract, food from the stomach that can be a Tranzyme sought a drug that would complication of diabetes but has no mimic that signaling action for treatknown cause in 33% of cases. Current ing postoperative ileus. gastroparesis drugs are only moderTranzyme used its proprietary ately effective and have neurological MAcrocylic Template CHemistry or other side effects, so TZP-101 and (MATCH) technology to find 102 have both been granted DEAD RINGER The drug candidates. In each of fast-track status by the Food & Tranzyme’s compounds, a short X-ray structure of Drug Administration, Peterson Arora’s macrocycletether links the two ends of a said. stabilized α-helix tripeptide together, giving 14Macrocycles aren’t a pana(blue) lines up nicely to 20-membered rings. Small cea, but their potential benefits with a model of an adjustments to that tether, such ideal helix (pink). should encourage medicinal as removal of an olefin and adchemists to consider them dition of a methyl substituent more often, Peterson told with specific stereochemistry, were crucial C&EN. “It’s time for macrocycles to befor improving compounds’ solubility, halfcome more visible in drug discovery. More life in blood plasma, and more, Peterson, an people should know about the power of organic chemist, explained at the meeting. this structural class.” ■
THAT’S WHAT happened at Tranzyme Pharma, a biopharmaceutical company based in Research Triangle Park, N.C. Tweaking the tether component in a macrocyclic compound helped Tranzyme find its most advanced drug candidate, a therapy designed to get patients’ bowels moving again after surgery. The molecule, called TZP-101, has completed Phase IIb clinical trials.
£ää¯ÊV *Ê > Õv>VÌÕÀi`Ê
ÊÌiÊ1°-°°
Flash Chromatography System
iiÌÃÊ1-*É *É *É*É -ÊÀiµÕ Àii ÌÃ
RevealX™ Others
UÊ Õ Ê* ë>ÌiÊ L>à VÊ UÊ Õ Ê* ë>ÌiÊ L>à VÊ É UÊ Õ«À VÊ-Õv>ÌiÊ*iÌ>Þ`À>ÌiÊ1-* UÊiÀÀ ÕÃÊ Õ Ê-Õv>Ìi UÊ >}>iÃiÊ-Õv>ÌiÊ Þ`À>ÌiÊ1-*É *É UÊ* Ì>ÃÃ Õ Ê* ë>ÌiÊ L>à VÊ É *É *É UÊ* Ì>ÃÃ Õ Ê* ë>ÌiÊ L>à VÊ1-*É UÊ* Ì>ÃÃ Õ Ê-Õv>ÌiÊ *É UÊ- ` Õ Ê >ÀL >ÌiÊÞ`À ÕÃÊ É *É*É -
™
RevealX Technology* Exposes Previously Undetected Compounds
UÊ- ` Õ Ê >ÀL >ÌiÊ Þ`À>ÌiÊ É UÊ- ` Õ Ê* ë>ÌiÊ L>à VÊ Þ`À>ÌiÊ1-*É *É UÊ- ` Õ Ê* ë>ÌiÊ L>à VÊÞ`À ÕÃÊ1-*É *É UÊ- ` Õ Ê* ë>ÌiÊ L>à VÊi«Ì>Þ`À>ÌiÊ1-*É UÊ- ` Õ Ê-Õv>ÌiÊÞ`À ÕÃÊ1-*É -
*patents pending Grace Davison Discovery Sciences
Reveal What You Have Been Missing
ÜÜÜ°ÃÌVi V>°V
'HWHFW0RUH&ROOHFW6PDUWHU6XEPLW)DVWHU *HWLW5LJKWWKH)LUVW7LPH Go to: www.discoverysciences.com/reveleris
"-/Ê Ê "°
1 /1, ,Ê"ÊÊ*1,/9Ê
",
R&D 100 2009 Award Winner
ALLTECH® is a trademark, registered in the United States and/or other countries, of Alltech Associates, Inc. REVELERIS™, and REVEALX™, are trademarks of Alltech Associates, Inc. GRACE®, and GRACE DAVISON® are trademarks, registered in the United States and/or other countries, of W. R. Grace & Co.-Conn. GRACE DAVISON DISCOVERY SCIENCES™ is a trademark of W. R. Grace & Co.-Conn. This trademark list has been compiled using available published information as of the publication date of this brochure and may not accurately reflect current trademark ownership. Alltech Associates, Inc. is a wholly owned subsidiary of W. R. Grace & Co.-Conn. Grace Davison Discovery Sciences is a product group of W. R. Grace & Co.-Conn., which now includes all product lines formerly sold under the Alltech brand. © Copyright 2009 Alltech Associates, Inc. All rights reserved. The information presented herein is derived from our testing and experience. It is offered for your consideration and verification. Since operating conditions vary significantly, and are not under our control, we disclaim all warranties on the results that may be obtained from the use of our products. W. R. Grace & Co.-Conn. and its subsidiaries can not be held responsible for any damage or injury occurring as a result of improper installation or use of its products. Grace reserves the right to change prices and/or specifications without prior notification.
Ê - / -
WWW.CEN-ONLINE.ORG
57
SEPTEMBER 7, 2009
COURTESY OF PARAMJIT ARORA
Macrocyclizations can be powerful tools for drug discovery, but the precise origins of enhanced binding affinities may vary with the system, Martin emphasized. To understand those reasons, it’s important to accurately measure enthalpies and entropies of binding with a technique such as isothermal titration calorimetry, he added. Whatever its origin, the modest bindingaffinity boost might still open up other options for the BMS team, Marcin noted. “A jump in potency lets you make changes elsewhere,” he explained. Make the right changes, and you could end up with a compound that goes all the way to clinical trials.
