BIRINAPANT, Apoptosis inhibitor
(2S,2′S)-N,N’-((2S,2′S)-((3S,3′S,5R,5′R)-5,5′-((6,6′-difluoro-1H,1′H-[2,2'-biindole]-3,3′-diyl)bis(methylene))bis(3-hydroxypyrrolidine-5,1-diyl))bis(1-oxobutane-2,1-diyl))bis(2-(methylamino)propanamide)
1260251-31-7 cas no
US20110003877,WO 2013049350 A1
| Molecular Weight: | 806.94 |
| Birinapant Formula: | C42H56F2N8O6 |
Birinapant, also known as TL32711, is a synthetic small molecule and peptido mimetic of second mitochondrial-derived activator of caspases (SMAC) and inhibitor of IAP (Inhibitor of Apoptosis Protein) family proteins, with potential antineoplastic activity. As a SMAC mimetic and IAP antagonist, TL32711 binds to and inhibits the activity of IAPs, such as X chromosome-linked IAP (XIAP) and cellular IAPs 1 and 2. Since IAPs shield cancer cells from the apoptosis process, this agent may restore and promote the induction of apoptosis through apoptotic signaling pathways in cancer cells. IAPs are overexpressed by many cancer cell types and suppress apoptosis by binding and inhibiting active caspases-3, -7 and -9 via their baculoviral lAP repeat (BIR) domains
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
(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
Credit: Courtesy of TetraLogic
It’s often said that two heads are better than one. For Malvern, Pa.-basedTetraLogic 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 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 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.
spectral data
1H NMR (300 MHz, CDC13): 511.74 (s, 2H), 8.27 (d, J= 8.7 Hz, 2H), 7.71 (dd, J= 5.4, 8.4 Hz, 2H), 7.55 (dd, J =2.4, 9.6 Hz, 2H), 6.88 (ddd, J= 2.4, 9.3, 9.3 Hz, 2H), 4.62-4.78 (m, 4H), 4.43 (dd, J= 9.3, 9.9 Hz, 2H), 4.03 (dd, J= 4.8, 11.4 Hz, 2H), 3.80 (d, J = 11.4 Hz, 2H), 3.66 (dd, J= 2.7, 14.4 Hz, 2H), 3.53 (dd, J = 11.4, 14.4 Hz, 2H), 3.11 (q, J = 6.9 Hz, 2H), 2.56 (s, 6H), 2.45 (m, 2H), 2.19 (d, J= 14.4 Hz, 2H), 1.76-2.10 (m, 6H), 1.59 (br s, 2H), 1.39 (d, J= 6.9 Hz, 6H), 1.22-1.38 (m, 2H), 1.07 (t, J = 7.2 Hz, 6H) ppm;
13C NMR (75 MHz, d6- DMSO): 5175.2, 172.8, 161.6, 158.5, 137.3, 137.2, 128.4, 128.3, 126.4, 120.8, 120.6, 109.4, 108.7, 108.4, 98.4, 98.0, 70.8, 60.2, 59.9, 56.6, 51.8, 36.4, 35.3, 28.3, 25.6, 20.0, 10.6 ppm.
Mass spectrum (ESI), m/z 807.5 [(M)+; calcd for C42H56F2N806: 806.9].
DR ANTHONY CRASTO
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