Posts Tagged → Gleevec
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.
This AM, Reuters released a special report about the state of drug R&D. Overall, I enjoyed reading the piece. Though there isn’t a whole lot in there that C&EN’s readers who work in the area won’t already know, I think the article does a great job of capturing how scientists- and young scientists in particular- feel about their job situation. The folks quoted in the article are feeling more than a little frustrated.
That said, there were a couple of statements in this article that were unfair, misleading, or downright pessimistic. In the section on biotech, we have this generalization:
Biotech’s “large molecule” protein drugs, made using genetic engineering, have proven superior at fighting complex diseases like cancer to many conventional “small molecule” chemical drugs.
That argument is a little hard to swallow. You might say that the side effects from a protein drug are more benign than those of traditional chemotherapies like 5-fluorouracil. And Herceptin, a biologic drug, has made a big difference for women with a specific type of cancer. But what about Gleevec? If you have cancer driven by a certain genetic mutation, Gleevec works-and it’s a small molecule.
Look closely at Herceptin or Avastin-a biologic cancer drug the Reuters article mentions in its next paragraph- and you’ll notice that for treating some cancers they must be taken with small molecules- carboplatin, paclitaxel, or something else. Both parts of the treatment- the small molecule and the protein- are necessary for the treatment to work its best.
Maybe cancer isn’t the best example- after all, every cancer is a different challenge. What about other diseases? In the past, we’d written about how biologic drugs are the best we’ve got for multiple sclerosis. Humira, a biologic treatment for rheumatoid arthritis, is another success story that the Reuters article mentions.
But what about HIV? There are an awful lot of small molecules on this list of approved HIV drugs, and when used correctly, they keep the disease at bay for years.
Yes, there’s some wiggle room in the Reuters statement because of the use of the word “many”. Maybe it’s the organic chemist in me speaking, but I get pretty miffed when I hear pessimistic statements about small molecules.
A smaller nitpick but a nitpick nonetheless- the article seems to use the words “biotech” and “biologic” interchangeably, which might confuse someone who isn’t familiar with the area.
By 2014, the world’s two top-selling prescription drugs won’t be tablets sold in blister packs but needle-based biotech treatments — Avastin for cancer, sold by Roche, and Humira for rheumatoid arthritis, from Abbott Laboratories — according to consensus forecasts compiled by Thomson Reuters.
Lastly, I wish the article hadn’t ended back in an academic setting. Instead, I would’ve liked to hear more about the scientists who migrated to Parexel, the company that conducts clinical trials for drugmakers. That academic ending was a downer to me- it represents a narrow-minded view about what the skills of a scientist trained to work in pharma are good for.