Galactose Conjugation Makes Navitoclax a Safer Senolytic Drug

If given a way to more effectively target senolytic drugs towards senescent cells, reducing off-target effects, then navitoclax is a good drug to test with. Navitoclax is arguably the worst of the first set of drugs found to be meaningfully senolytic; it certainly compares unfavorably with dasatinib. While navitoclax can kill a usefully large fraction of senescent cells in aged tissues, the dose required for that outcome will also kill a lot of normal cells along the way. More unpleasant drugs have since been discovered to be usefully senolytic, such as cardiac glycosides, but there is much less data on their senolytic use at this stage. In comparison, a good deal of data exists for the ability of navitoclax to destroy senescent cells. Its unpleasant side effects are quantified as a result of its development as a potential chemotherapeutic.

Finding ways to target highly toxic drugs to specific cell populations is a well established line of work in the cancer research community. Even if it were not the fact that many senolytic drugs were initially characterized for use as cancer therapeutics, it would not be surprising to find analogous cell targeting research taking place in the field of senolytics. This is a well understood approach to making toxic drugs more useful.

You may recall that researchers have been exploring the possibility of conjugating toxic drugs with galactose, producing a far less harmful prodrug molecule. Senescent cells are characterized by the high expression of senescence-associated β-galactosidase. This enzyme acts to remove the galactose from the prodrug, restoring the original toxic molecules that then kill the cell. In today's open access paper, an variant on this approach is demonstrated to improve the characteristics of navitoclax as a senolytic drug.

Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity

Recent research has identified targetable vulnerabilities of senescent cells that can be exploited by a novel group of drugs called senolytics. These compounds preferentially kill senescent cells by different mechanisms. Senolytics include the BCL-2 family inhibitors Navitoclax (ABT-263) and ABT-737; the flavonoid fisetin; combinations of tyrosine kinase inhibitors and flavonoids (e.g. dasatinib and quercetin); FOXO4-p53 interfering peptides; HSP90 chaperone inhibitors; and other compounds such as piperlongumine and cardiac glycosides. Senolytics have emerged as promising agents for treatment of pulmonary fibrosis, atherosclerosis, osteoarthritis, type 1 diabetes mellitus, type 2 diabetes mellitus, and neurocognitive decline. They can also rejuvenate aged hematopoietic stem cells and muscle stem cells and extend the lifespan of naturally aged mice.

Despite successful preclinical proofs-of-concept for senolytics, their potential translatability is hampered by their associated toxicities, necessitating the development of more specific, and less toxic, second-generation senolytics. Navitoclax has been validated in a variety of preclinical models showing high potency in killing senescent cells - however, it also has significant on-target haematological toxicity, including thrombocytopenia.

One consistent feature of senescent cells is their enrichment in lysosomes and lysosomal proteins, including senescence-associated β-galactosidase (SA-β-gal) which is widely used as a marker of senescence. We previously showed that the encapsulation of nanoparticles with galacto-oligosaccharides (GalNPs) is an efficient method to preferentially deliver cytotoxic drugs and tracers to the lysosomes of senescent cells where SA-β-gal activity digests the galacto-oligosaccharides, thereby releasing the cargo. We have also shown that a fluorescent probe covalently linked to multi-acetylated galactose is preferentially digested by senescent cells, releasing the free fluorophore.

Here, we have modified Navitoclax with an acetylated galactose to exploit the enriched SA-β-gal activity of senescent cells. Using a variety of model systems, we show that galacto-conjugation of Navitoclax, which we name Nav-Gal, results in a prodrug with selective, pro-apoptotic senolytic activity released in senescent cells that is dependent on GLB1 activity. Galacto-conjugation of Navitoclax reduces thrombocytopenia in treated mice at therapeutically effective doses, as well as apoptosis of platelets in human blood samples treated ex vivo. Overall, we propose galacto-conjugation of cytotoxic drugs as a versatile methodology for developing second-generation prodrugs with high senolytic activity and reduced toxicity. We provide evidence of the efficacy of combining senescence-inducing chemotherapies with senotherapies in cancer, with potential for clinical application.

Comments

I tried fisetin for early onset osteo arthritis in my left knee (broke it as a teenager), but it didn't seem to do anything. Might have to figure out how to get dasatinib to give it a go with quercetin.

Posted by: Jimofoz at April 10th, 2020 8:36 AM

@Jimofoz
How much time did it past after your have taken it? Did you try fasting? For the very least reduced weight helps

Posted by: Cuberat at April 10th, 2020 3:08 PM

With Insilico-like game changing, we could have 1000 senolytics in market by 2030. Choosing a good combination of 20 senolytics or so could probably add easily 5 years of life expectancy. If you add other developments, gene therapy, stem cells, ect... We will hit LEV in the 2030s easily.

Posted by: Jonathan Weaver at April 13th, 2020 7:44 AM

@Jonathan Weaver

Given that how quickly the first Senolytics were discovered it is surprising that we don't see a new one if not every month, at least every half a year. Unless everybody is working in stealth mode that would mean that there are either insurmountable difficulties or not enough interest...

Anyway, conjugating a compound seems patentable, so is a target for investment.

Posted by: Cuberat at April 13th, 2020 1:12 PM

Hi there! Just a 2 cents.

Senolytics are great in the mean time, I don't wish to be a downder, but to nuance there is a substantial difference between a few years lifespan extension and reaching extreme longevity (like LEV). Senoyltics will give a few years of healthy life (and thus a longer lifespan, in the average, but a longer average is a good thing). I don't see seloytics increase maximum lifespan (or by much). IT is because remove senescent cells does not make mice live extremel lifespan
(it gives 20% healthspan avg. extension and 10 or so maximum extension in mice that have
p16-positive senescent cells ablation. And, we know that effects in mice are much stronger than in humans -> less translatable to humans, I wager 25-33% of the effect in mice will be in humans). It's not so much the senescent cells doing SASP the problem (on maximal age, but is helpful in average age); it's them becoming senescent, replicative senescent due to Hayflick in the first place, which will mean cell division/cycling arrest for dividing cells. (Not talking about spontaneous senescence or oncogenic senescence which are 'premature exit' of cell cycle; not 'aging passages/divisions' over time/years as is replicative senescence). And this causes epigenetic drifting. Which that is completely causal to aging. The more I think about it, the more I think LEV is impossible unless we are very clever and 'circumvene' many catch22s/use hacks to make 'just enough rejuvenation - repeatedly' possible. The chance of a person of 100 years old reaching LEV is nearly nill, but a person of 0-20 years old, right now, as a decent-to-not so decent chance of reaching LEV later if it ever comes. I see (if it happens) it happening in ±2050, not 2030-40, way too quick (it is not 'quick'..but by medical science - it is...we would want in 1 year if we could have it, alas...). Bureaucratic slowmo progression/cog in the wheels in reason why it will take an additional 15-20 years - On top of finding the solution (thus 25-50 years is reasonable and the more time goes...the More Time/work Adds...

''Work Expands as Time Goes''.

Unforeseen problems - will come and will slow down tings.

I would love it that they find in 2030-40...but, it is such an immense find if they do find it/cure aging; that it will the biggest invention in humanity - it will not 'be given' immediately (though it Should be...to save lives/old people), but it rarely works like that. It is always 'guarded' (rich people are ones getting access because rich, poor people/mass it will be later) tested a million times in 1,000,000 clinical studies on humans - Before - it reaches public...that takes time and $$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$ (add a 10+ years).

Just a 2 cents.

PS: It is possible that LEV is only possible in a Young body and that an aged person need 100% reversal of everything which is Quasi unfesable unless there is complete reversal of everything in that aged person. Only 'Young/slow growing' animals live ultra-life longspans. Aged animals rarely if ever 'outbeat' the maximum of the specie - because too late. (Of course that is if we do Nothing, but with therapies of the future, maybe we might be able to reverse clock, reverse damages, reverse Junk, reverse morphodynamics, reverse everything in old people - and make them Young body again. It may be utopia, but if we can't, Young people will benefit immensely, and they have the possibiliyy of living 500 years or more; because they are stll Young and 'keep' that body intact for centuries 'as young' - on the clock, damages, etc...). Maintenance is the biggest predictor of maximal and avg. lifespan; maintenance to Young epiclock, maintenance to low DNA damage levels, maintenance of telomere length, and so forth. Just like the 'repair a used car' analogy, but more nuanced because there are so many catch22s in it than simply repair and solved. If it had been this simple we would have Long ago cured aging.

Posted by: CANanonymity at April 13th, 2020 7:45 PM

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