14 replies to this topic

[r06ue1]

I am looking for info from anyone on these boards that has any knowledge of the chemical compound TDZD-8 (4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione).  

 

I stumbled on this compound from an article Scuba had linked a few months ago and began doing my own research on it.  It appears that this compound kills LSC's and progenitor cells and has been known to do this since at least 2007.  I have been unable to find any evidence of this being taken to trials and the only company I found that is pursuing it currently is a little unknown company called Panther Biotechnology (http://pantherbiotechnology.com/) whose stock is currently trading at $0.94.  The compound appears to be in use or studied for other things also (see below).  If you have anything to add, it would be much appreciated.  

 

Here are some excerpts from articles I have dug up in my research:  

 

 

Studies of TDZD-8 were performed to determine the effects on different types of leukemia 

 

cells taken from patients (AML, bcCML, CLL and ALL), and on normal blood cells as well. 

 

All forms of leukemia cells were strongly inhibited and induced to die by TDZD-8, 

 

however, there was minimal effect on normal blood cells. 

 

 

This pattern of selectivity continues with the third agent, TDZD-8, which is lethal only 

 

to the leukemic population.  

 

https://www.ncbi.nlm...les/PMC1988840/

 

 

Rapid and selective death of leukemia stem and progenitor cells induced by the compound 

 

4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8).

 

Leukemia is thought to arise from malignant stem cells, which have been described for 

 

acute and chronic myeloid leukemia (AML and CML) and for acute lymphoblastic leukemia 

 

(ALL). Leukemia stem cells (LSCs) are relatively resistant to current chemotherapy and 

 

likely contribute to disease relapse and progression. Consequently, the identification 

 

of drugs that can efficiently eradicate LSCs is an important priority. In the present 

 

study, we investigated the antileukemia activity of the compound TDZD-8. Analysis of 

 

primary AML, blast crisis CML (bcCML), ALL, and chronic lymphoblastic leukemia (CLL) 

 

specimens showed rapid induction of cell death upon treatment with TDZD-8. In addition, 

 

for myeloid leukemias, cytotoxicity was observed for phenotypically primitive cells, in 

 

vitro colony-forming progenitors, and LSCs as defined by xenotransplantation assays. In 

 

contrast, no significant toxicity was observed for normal hematopoietic stem and 

 

progenitor cells. Notably, cell death was frequently evident within 2 hours or less of 

 

TDZD-8 exposure. Cellular and molecular studies indicate that the mechanism by which 

 

TDZD-8 induces cell death involves rapid loss of membrane integrity, depletion of free 

 

thiols, and inhibition of both the PKC and FLT3 signaling pathways. We conclude that 

 

TDZD-8 uses a unique and previously unknown mechanism to rapidly target leukemia cells, 

 

including malignant stem and progenitor populations.

 

https://www.ncbi.nlm...pubmed/17785584

 

 

TDZD-8 is a non-ATP competitive inhibitor of GSK-3β.

It is widely studied as a cytoprotective agent to treat septic

and nonseptic shock, lung injury, arthritis, spinal cord

injury, colitis and Alzheimer disease. Guzman et al. explores

another functional facet of TDZD-8, namely selectively

killing AML-stem/progenitor cells. Cellular and molecular

studies indicate that its mode-of-action is correlated with

rapid loss of membrane integrity, depletion of free thiols/

rapid ROS generation and inhibition of both the PKC

and FLT3 signaling pathways. It should be noted that

TDZD-8 induces cell-death effects not only on AML,

but also chronic myeloid leukemia (CML) and acute

lymphoblastic leukemia (ALL) (25).

 

From:  

Reactive oxygen species in eradicating acute myeloid leukemic

stem cells

Hui Zhang1,2, Hai Fang1, Kankan Wang1

 

 

LSC defenses breached by chemical arsenal

http://www.bloodjour...so-checked=true

 

Tessa L. Holyoake (2007) (UK Scientist which is working on the CML Cure)

 

 

Rapid and selective death of leukemia stem and progenitor cells induced by the compound 

4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8)

https://www.ncbi.nlm...les/PMC2234782/

[Trey]

I have not heard anything more about TDZD-8 since 2007 when it was first suggested as a leukemia drug, and cannot find any clinical trials which have tested it.  It was supposed to be a Parkinson/Alzheimers drug, but I don't know if it ever went anywhere.  It acts on the nerves, mainly.  I doubt it would be useful in CML due to side effects on the nervous system. 

[kat73]

This looks pretty darned interesting - how do we go about finding out?  It looks like your research is about all there is in print.

[r06ue1]

I'm going to continue to dig around, may end up contacting Panther to see what the status is of their trial.  Kind of disconcerting that no trials have been done on this yet, hope it is like Trey said and that they found it causes nervous system problems or other bad side effects (but with no trial, how would they know?).

[scuba]

From their website:

 

"TDZD-8 is a kinase inhibitor and induces oxidative stress, causing its striking ability to induce the leukemia cells to die after less than 2 hours of exposure to the drug.  TDZD-8 has demonstrated broad and selective in vitro activity against many different types of leukemia. In addition, TDZD-8 has no significant toxicity in normal hematopoietic stem cells."

 

The key phrase used is "in vitro", which means tested in a petri dish. Going from in vitro to in vivo (in animals) is a big step. Many drugs work great "in vitro" and fail in vivo. TDZD-8 may be one of them - especially if it has nerve system toxicities. It's been eight years - so short in the life of drugs like these. 

 

Linked below is a 2015 press release announcing the licensing of TDZD-8 rights from Univ. of Rochester.

 

http://www.marketwir...bya-2010865.htm

 

Panther evidently see promise in the drug, but it is a LONG way from commercialization given the time frame already passed and the fact that a Phase I trial hasn't started (toxicity).

[r06ue1]

In vivo was completed (on mice) in 2007, not sure if there is another step after that other than Humans.  

[r06ue1]

 

 

NOD/SCID mouse assays

NOD/SCID mice were sublethally irradiated with 2.7 Gy (270 rad) using a RadSource-2000 x-ray irradiator before transplantation. Leukemia cells for NOD/SCID analysis were obtained from PB specimens, and normal cells were obtained from CB specimens. Cells to be assayed were injected into the tail vein (5-10 million cells) in a final volume of 0.2 mL of PBS with 0.5% FBS. After 6 to 8 weeks, animals were killed, and BM was analyzed for the presence of human cells by flow cytometry.

[scuba]

In vivo was completed (on mice) in 2007, not sure if there is another step after that other than Humans.  

 

I wonder what happened to the mice ... they haven't been heard from since ...

[gerry]

Probably taking a nice holiday on a farm somewhere, just like your pets when you were little. :-)

[r06ue1]

 

Just to clarify in case of any confusion, TDZD-8 did not kill the mice used in the experiments, the lab killed them so that they could be dissected.  End result is the mice died though.  

[scuba]

... poor mice. At least they went to a better place.

 

[r06ue1]

I have sent Panther an Email requesting additional information on their trial.  

 

I have also found that this chemical compound is currently in use to treat Alzheimer's disease (phase IIb or higher trial status), albeit a slightly modified form of the base chemical.  I am still researching whether it is being used in any other medications and found that it is easily acquired on the Internet for a (hefty) price (most chemical manufacturers produce it for experimentation).  

 

No, do not go out and buy it and take it or make it in your own lab.  

[r06ue1]

Okay, I hope I am wrong here and I don't want to be the tin foil hat type, but it appears there is movement to keep this drug from ever coming to market.  

 

Panther Biotechnology, Inc. was purchased by another company (Brown Technical Media Corp.) which has nothing at all to do with pharmaceuticals and all mention of the TDZD-8 trial has been removed.  

 

I'll continue to keep an eye open for any change.  

 

I also read that this compound may work on type 2 diabetes.  

 

 

The serine/threonine kinase GSK-3 is a conserved signaling molecule with essential roles in diverse biological processes. Aberrant GSK-3 activity has been linked with several human diseases including diabetes, inflammation, and neurodegenerative and psychiatric disorders...

 

https://www.ncbi.nlm...les/PMC3204427/

 

Also, I edited a previous post on this topic to make mention that the mice given TDZD-8 did not die from the compound but were killed by the lab for dissection.  There has been no mention of TDZD-8 being harmful to living mice.

[r06ue1]

Okay, so I heard from a researcher (no names) on this topic.  The researcher reported that TDZD-8 was found to be just as toxic to normal cells and they stopped using it, however, they did make mention that if a drug company doesn't want them them working on certain molecules, than they don't.  Found that last part very interesting and was happy that they shared that tidbit with me.  

 

Still find it curious that they are using TDZD-8 in other trials (ongoing), especially with the brain.

[scuba]

No surprise on TDZD-8. Most drug candidates never make it past Phase I trials let alone surviving Phase II,III,IV and then approval.

in fact, only ~5% of all drugs that make it to a clinical trial setting (i.e. rats were successful first) go on to approval.

 

https://www.bio.org/...mplion 2016.pdf

 

For each drug that makes it - literally hundreds of drug candidates fail. Most never make it to a clinical trial. And as stated above - of those that do, only 5% make it to approval.