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ABT-199 Nears Its Finish Line

A couple of years back, AbbVie ran into an unusual problem in the clinic. Their Bcl ligand, ABT-199, was working a bit too well, and killing off so many leukemia cells that the resulting cellular debris was causing kidney trouble in some patients. The company immediately started working on clinical protocols to get things restarted, and I’m happy to report that the compound seems to be meeting its endpoints in its current trial, and the company (and its partner Roche) say that they will be filing soon for FDA approval.

This will not only be a real step forward in chronic lymphocytic leukemia (CLL), and potentially several other forms of leukemia, lymphoma, and myeloma, it’ll be a real step for medicinal chemistry as well. These Bcl-targeted compounds are pure protein-protein interaction (PPI) inhibitors, a class of drug that’s historically been a hard slog. It’s still a tough way to make a living – the Bcl system has a very nicely defining binding groove in it, which helps – but over the years, more and more research organizations have been banging away at this sort of target. (Some have even been thinking about ways to do the opposite – making protein-protein interactions even more stable than they are already).

There are hundreds of thousands of these interactions going on in living cells. I don’t know what percentage of those are “druggable” (no one does), but we’ve only just begun to figure out how to do it. And I don’t know how many big, general discoveries are waiting in this area, because the variety of protein interaction surfaces is pretty impressive. But you can’t rule out such things, either. We know that PPI-based drugs are possible; now we could use some breakthroughs to make them a little more likely.

9 comments on “ABT-199 Nears Its Finish Line”

  1. JeffC says:

    I know some companies (cough cough, Pfizer. Cough cough, AZ) who would never have developed that compound. Aniline. Exposed double bond. Nitro. Aghhhhhh, run away! No, no, these would never pass the filters that control everything. But hey, Abbott are in the game of getting compounds onto the market, so good luck to them.

  2. anon the II says:

    I think I’d call Cyclosporine, FK-506 and rapamycin, drugs that stabilize PPI. It’s unfortunate that these happen to be natural products and pharma sorta doesn’t do that much any more.

  3. Pete says:

    Some companies have found it easier to discover drug-likeness metrics than drugs. However, I am convinced (I really am coughing) that the cellular debris problem constitutes unequivocal validation of ligand efficiency as a metric (reviewed in the blog post that I’ve attached as URL) for this comment and I believe that it was careless of them not to measure the singlet oxygen quenching/scavenging ability of this compound before taking it into clinical development.

  4. Andy II says:

    “….pure protein-protein interaction (PPI) inhibitors, a class of drug that’s historically been a hard slog. It’s still a tough way to make a living –”

    Is this what exactly the most antibody-based drugs do as the primary functions, right?
    It will be great if we would find a way to design “smaller molecules” as drugable inhibitor of PPI but we may not have to stick to a concept of “small molecule-based” PPI inhibitors…. No?

  5. David Borhani says:

    “Locking” drugs: Cyclosporine, FK-506, & rapamycin, as anon the II mentioned; Taxol/taxotere/paclitaxel, ixabepilone (tubulin/microtubules); topotecan, etc. (topoisomerase I/DNA); etoposide (topoisomerase II/DNA); ciprofloxacin, etc. (gyrase A/DNA); fusidic acid (ribosome/EF-G/tRNA). There may be other approved “lockers” I’m unaware of.

    “Locking” non-drugs: forskolin (adenylate cyclase); brefeldin A (Arf.GDP/Arno [Sec 7]); various plant hormones: auxins & jasmonates (ubiquitin ligase components), gibberellic acid (transcription factors), abscisic acid (PYL1/PP2C); etc, etc.

  6. julie says:

    can someone explain how can this cmpd get to where it’s now with NO2, double bond and aniline?

  7. Design Monkey says:

    @julie: No problem.

    1. it’s anticancer field. Anything goes there. Look at mechlorethamine. One could easily pack it into bombs and throw at enemy as a decent chemical weapon.

    2. features you noted, in this molecule are not especially evil. “Aniline” there is the same kind of “aniline” as in all sulfonamide drugs (several tens of them). Double bond – a bit of metabolic risk and epoxide formation risk. Still rather substituted one, so probably not too big a problem. Nitro – ok, that’s a bit rare nowadays, but, again, nothing that anticancer med could not chew and use.

    3. also anticancer meds generally are not intended for longterm chronic use. That too allows to get away with things, that would not be acceptable in other applications.

  8. aairfccha says:

    Anyone knows what they actually did to address the problem, lower dose?

    In general, could you pull the cancer breakdown products out of the blood by dialysis? I guess getting approval for a drug requiring this even as precaution might be a challenge but as last ditch chemotherapy…

  9. somebody says:

    @aairfccha… They started out with a low dose to prime and slowly ramped up to the target dosage.

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