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PARP Inhibitors Do It Again

When we last looked in on the long-running saga of PARP inhibitors around here, Tesaro had posted excellent clinical results for their compound and re-invigorated the whole field. At the time, I wrote “It’ll be quite interesting to see the clinical results of the other PARP compounds in this light. You’d expect more differences to become apparent as they are tried in combination with other agents, too.” We now have some more data that bear on both those statements.

AstraZeneca has reported more data on their own compound (Lynparza, olaparib) in ovarian cancer (where Tesaro’s compound niraparib, which used to be Merck’s compound, had performed so well). And the AZ compound delayed progression of ovarian cancer for two years compared to placebo. As that first link in the paragraph (from Adam Feuerstein) mentions, though, this is very similar data to the Tesaro trial, and the two trials were different enough that the two compounds may be functionally identical. So we now know that other PARP compounds can be equally effective, but there may not be such big differences, in the end. If such emerge, it might well be in combination regimens or in side effect profiles. The biggest problem with hitting PARP seems to be anemia, so that will be worth watching to see if one of the entries can differentiate itself out in clinical practice.

I had mentioned Clovis and their PARP inhibitor (Rubraca, rucaparib), which used to be Pfizer’s compound, and Clovis got approval for that just at the end of last year – again, for ovarian cancer. Feuerstein makes the point that this news is probably best for them, since they’re the smallest company with an approved drug, and it looks like they can probably ride on the results of these larger trials, in the anticipation that their compound is just as good as anyone else’s. Tesaro is hoping to get approval soon for niraparib, and Pfizer has an entry, too, ironically. After ditching their own compound to Clovis, they found themselves with another PARP inhibitor (talazoparib) when they bought Medivation (for other reasons), just in time for these compounds to become valuable again. It’ll be a crowded market, but women with BRCA-mutated ovarian cancer are going to benefit a great deal.

As an aside, it’s worth following those links above to the individual compounds to have a look at their structures. They are some of the most “med-chem” compounds you could ever want to see, at least to my eyes. And while they all have similarities, they all have somewhat different features as well. That just shows you how many ways there are to skin the cats in this business, since all of these compounds look to eventually make it through into the market.

22 comments on “PARP Inhibitors Do It Again”

  1. DCRogers says:

    To all computational chemists out there, I’d love to see the 3D pharmacophore model that fits this diverse set of molecules!

    Not being snide — I really *would* like to see it…

    1. ScientistSailor says:

      Look in the PDB there are > 100 structures of PARP, many with inhibitors bound.

  2. Hap says:

    It’s good to hear about drugs (let alone small molecules) that aren’t going down in balls of flame.

  3. Barry says:

    Seems that a PARP inhibitor (or even more so, a PARP inhibitor in combination with a drug that creates DNA breaks) is a retreat from the strategy of targeting the defects that drive a cancer, towards the older oncology mode of clobbering any cell that dares to attempt replication.

    1. Toby says:

      Not exactly, because PARP inhibition is synergistic, i.e. has much bigger effect, in combination with BRCA1/2 deficiency. So you’re targeting a quite specific population of cells.

  4. Binding efficiency fan says:

    Derek, I agree with your comment about the drug-likeness of the PARP inhibitors. AbbVie’s veliparib that isn’t on your list is an incredibly efficient structure as well.

  5. anon says:

    All the structures except one has fluorines. Interesting.

    1. anon2 says:

      As to the fluorines present, anon, likely they boost metabolic stability. 20% of all small molecule drugs have fluorines, and closer to 50% of drugs launched in the last decade

  6. Lane Simonian says:

    All that I can say is that PARP inhibitors can potentially help in the treatment of a variety of diseases.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2438280/

  7. Chad Irby says:

    PARP is serious business, but…

    A while back, I was at a presentation on the subject, and the presenter said “PARP” just a little weird. Someone laughed. Which started a chain reaction in the audience. By the end of the presentation, half of them would giggle whenever he said “PARP.”

    Just one of those things, I guess…

    1. Nate says:

      I struggle to imagine how anyone would pronounce it in any other way than “rhymes with harp”.

      1. Chad Irby says:

        He sort of inhaled/swallowed when he said it the first time.

        Like “Pu-haaaaarp.” It’s hard to describe.

        Funny, though.

  8. pi* says:

    why do all the drug names end in ‘carib’?

    1. Derek Freyberg says:

      As Isidore said, because they are PARP inhibitors (PARp inhIBitors, to tweak the cases). WHO (and USAN, locally) have lists of prefixes, “infixes” (middles), and suffixes for drug naming, and “parib” is almost certainly the approved suffix for PARP inhibitors. You can send USAN any proposed generic name you like, but if you have a new PARP inhibitor and want a name that doesn’t end in “parib”, you almost certainly won’t get it.

  9. Isidore says:

    You mean “-parib”, as in niraparib, olaparib, rucabarib, right? It indicates (unsurprisingly) a PARP inhibitor.

  10. Me says:

    Yep – and ‘-inib’ for kinase inhibitors, and ‘-mab’ for…well..mAbs are the obvious ones. Not sure if ‘-statin’ implies mechanism of action or not.

    1. Isidore says:

      Below is a link to a long list, some stems are related to mechanism some not.
      https://druginfo.nlm.nih.gov/drugportal/jsp/drugportal/DrugNameGenericStems.jsp

  11. Mike B. says:

    NIH budget being cut by nearly 20%. Good bye US science, hello China.

    How long does it take to learn Mandarin for someone over 25?

    1. johnnyboy says:

      Not sure you should worry too much about China, as they mainly copy whatever US research does, or make up fake research to get jobs. Normally I’d have thought this would signal leadership in research moving towards Europe, except that Europe is currently busy shooting itself in the head. So I think it’s just global science that’s on the decline. But not to worry, I’m sure there’s plenty more cool phone games coming !

      1. JAB says:

        Not yet….that’s the Trump skinny budget. The Congress writes and approves the budget and many in Congress are turning up their noses. As it is, all of it is supposed to come from Global Health and the Fogarty Center, which deals with international affairs more generally, like foreign postdocs (!). I can’t for the life of me see how they can get that much of a cut with those two priorities, though. I think the NIH budget will end up level in the end.

        1. Jane says:

          It’s supposed to be business style negotiation. If you want a modest cut then propose a drastic cut and let your opponent talk you down to a modest cut. Then he/she thinks they won while in reality you got the modest cut you wanted all along.

  12. Richard Bernstein says:

    I discovered Poly ADP Ribose Polymerase (PARP). In grad school I fractionated a Nuclear Extract from HeLa cells over a phosphocellulose column and analyzed the fractions for transcriptional activity, just like my mentor Bob Roeder. I found one of the fractions stimulated transcription, but it wasn’t supposed to. I showed it to Roeder and he said “you just discovered polyADP ribose polymerase” in other words, same artifact HE found when he was in grad school.

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