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Replies to post #363367 on Anavex Life Sciences Corp (AVXL)
06/16/22 6:18 AM
06/16/22 7:34 AM
06/16/22 7:37 AM
Disclosure: I/we have a beneficial long position in the shares of AVXL.
06/16/22 8:32 AM
Anavex2-73 is a S1R agonist with moderate affinity and has produced impressive clinical results from double-blinded studies treating Rett syndrome and Parkinson disease dementia. Currently it is in a phase II/III trial for Alzheimer’s disease. However, neither the scientific nor the investment communities are fully endorsing the clinical results or the potential in AD treatment. Granted, there are thousands of agonists of S1R with higher affinities than that of Anavex2-73 and none of them have been proven to have significant clinical applications. Is Anavex2-73 unique?
Figure 2. Possible binding mode of Anavex2-73 to the active site of FKBP12.
Agonism to S1R will provide temporary relief of ER stress (ISR) and we can expect short-term improvement in symptoms resulting from AD. However, a sustained response requires blunting the source of inflammation, necroptosis. From a structural perspective, Anavex2-73 features a phenyl group (Benzene) adjacent to a 5-membered ring, a structural similarity to that of Phe-Pro dipeptide. FKBP12 recognizes and prefers a substrate with sequence containing Phe-Pro for catalyzing the isomerization of the corresponding peptide bond³?. We suspect that Anavex2-73 is an inhibitor of FKBP12 and subsequently conducted preliminary docking experiments. The results indicate that Anavex2-73 might be an inhibitor of FKBP12 (Figure 2) with reasonable affinity, likely in the nanomolar range. Granted, wet lab experiments are needed to confirm or disprove the docking studies, as docking alone does produce artifacts. However, the fit to the active site is intriguing, especially the impressive hydrophobic interactions between Anavex2-73 and the active site without steric strains. Further laboratory investigation is warranted to obtain binding affinities. Maybe it is too condescending to ask “Did Anavex stumble onto the right compound”?
(Lay Summary: There are thousands of S1R agonists around. Why Anavex2-73 seems to work better. Our modeling studies suggest that Anavex2-73 is unique in that it could also be a potent FKBP12 inhibitor, even Anavex (the company) is not aware of it! Most likely Anavex2-73 will succeed in clinical trial in AD because it works in both pathways!)
Have we finally found a compound that can do both, activate S1R and inhibit FKBP12? Is there light at the end of the tunnel in AD drug development? All of us are waiting with abated breath for the trial results from Anavex. Maybe, just maybe, we can relax knowing the mechanisms of Anavex2-73. The possible dual actions of Anavex2-73 might project altered course of disease progression as well as improved memory and cognition for AD patients.
(Lay Summary: Upon laboratory confirmation of the modeling studies, Anavex2-73 could change the way we treat or see Alzheimer’s disease. It could restore memory function and completely change the trajectory of disease progression. As a matter of fact, it should work on other diseases as well such as Parkinson’s, ALS, Fragile X syndrome, Rett, and possibly others. As for the ongoing trials, the results could be so spectacular that we would have never expected!)
06/16/22 9:00 AM
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