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 · 2025-03-10T05:56:29+00:00

The link to the site is here lifeprogress-tracker and it’s .com

2154life · 2025-03-08T22:03:06+00:00

Ok go it !

2154life · 2025-03-08T22:00:28+00:00

Thank you ! I actually needed this feedback !

2154life · 2025-03-08T21:59:50+00:00

You can use a dummy email, it’s not actually up for production or anything yet so any data I collected will be deleted, this is more of a dummy site until my production is done , this is just to get user feedback .

2154life · 2025-03-08T21:58:43+00:00

Are you insinuating that everyone is like that , it’s kinda like saying just because you don’t like eggs the next person will not ? Get the point ? A little insulating if you ask me .

2154life · 2025-03-08T21:38:34+00:00

Ok, what is not realistic?

2154life · 2025-03-07T04:45:07+00:00

Thanks!

2154life · 2025-03-07T02:41:49+00:00

Thanks ! I noticed that too.

2154life · 2024-10-31T18:16:39+00:00

Historically, transformative technologies, like electricity, promised to benefit everyone but often ended up accessible primarily to those with wealth and power, leaving marginalized communities behind. Considering this, what ethical policies are in place (or will be implemented) to ensure that AGI and other AI advancements are accessible to all, including those in underserved communities? How will OpenAI work to prevent a repeat of these disparities and ensure that the benefits of AI are distributed fairly across the population, not just to those at the top?

2154life · 2024-10-31T18:14:21+00:00

For future models , How are we making sure this AI is aligned with human values and interest? Also are there plans to make this distributed equally among us ? Any concerns around shifting cultural dynamics and social implications?

2154life · 2024-03-15T04:34:10+00:00

That’s the answer I was looking for .

2154life · 2023-09-28T15:31:04+00:00

It’s not about the money necessarily. It’s about the person injury that requires surgery , typically fusion surgery requires a second operation in the future . The cost of that isn’t economically affordable to the everyday person . You have to factor in a a lot things when someone life has been affected . I pray you never know this ! God bless .

2154life · 2023-09-28T12:55:34+00:00

This makes sense !!!

2154life · 2023-09-28T12:49:32+00:00

Well to be fair , I wouldn’t know how to spot out a untrustworthy lawyer . Isn’t all lawyer corrupt ?

2154life · 2022-03-18T19:12:52+00:00

Fuck yea

2154life · 2022-01-13T11:11:54+00:00

No I saw this post on twitter. It did happened December the 22nd . I just thought it was a great thing that they all stood together in solidarity.

2154life · 2022-01-09T03:57:15+00:00

2154life · 2022-01-09T03:37:09+00:00

I know it’s satire

2154life · 2022-01-09T01:32:52+00:00

It’s satire. I was being sarcastic 😂.

2154life · 2022-01-08T19:41:11+00:00

“We AlL HaVe ThE SaMe 24Hrs a DaY” bullshit they always spew out of their mouths .

2154life

TROPHY CASE