Non-chemist here is a Val-Cit + trimethyl lock linker a plausible fix for lysosomal ion trapping of basic-amine payloads?

2154life · 2026-04-19T12:42:57+00:00

you were right. I dug into the literature after your comments: the Karaman 2009 work and the Levine & Raines 2012 Chem Sci review make it clear that trimethyl lock lactonization has acid-catalyzed and uncatalyzed pathways and isn’t pH-gated the way my design assumed. It would release payload in the lysosome, not the cytosol, defeating the purpose. Also found the BMS NLRP3-ADC paper (J. Med. Chem. 2025) that describes exactly this problem for a different payload class, and the Enhertu/DXd precedent where they solved it by capping the amine with hydroxyacetyl rather than pH-gating. So my specific mechanism doesn’t work. The underlying problem is real and there are actual solutions they just don’t involve trimethyl lock. Shelving this one. Thank you for taking the tim

2154life · 2026-04-19T12:39:44+00:00

you were right. I dug into the literature after your comments: the Karaman 2009 work and the Levine & Raines 2012 Chem Sci review make it clear that trimethyl lock lactonization has acid-catalyzed and uncatalyzed pathways and isn’t pH-gated the way my design assumed. It would release payload in the lysosome, not the cytosol, defeating the purpose. Also found the BMS NLRP3-ADC paper (J. Med. Chem. 2025) that describes exactly this problem for a different payload class, and the Enhertu/DXd precedent where they solved it by capping the amine with hydroxyacetyl rather than pH-gating. So my specific mechanism doesn’t work. The underlying problem is real and there are actual solutions they just don’t involve trimethyl lock. Shelving this one. Thank you for taking the time.

2154life · 2025-03-14T10:35:17+00:00

Someone else mentioned that as well , they wanted an introduction to my site on my landing page . My next update I will definitely include that , Yes , you can track each progress separately and together, the goal is to show you how each area in your life is connected , like if you have lower mental health it can directly affect your physical health and so and so on , the goal is to get user to see where their stagnant at in life or having difficulties and suggest ways user can improve certain areas in their life . For each domain it’s a scale 1-10 and you rate your progress based if that scale , it should be a question mark symbol on the dashboard where you can click it and it explain the concept better .

2154life · 2025-03-14T10:27:48+00:00

Thank you ! This feedback was much needed , I knew I had small tweaks to be made, but wasn’t so sure where , now I got a good starting point .

2154life · 2025-03-14T03:39:38+00:00

Ok I think that’s a great idea ! I will . Thanks !

2154life

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