RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:Whats this?The slide with that info (#62)was at the end of the intro part of Dr. Beliveau's presentation. Following that, he first discussed TH-1904 and then had a third section on TH-1902. So, things have changed since that presentation as TH-1902 has taken the lead and was at the end of his remarks back in October 2019.
qwerty22 wrote: It's th1902? Because the patent clear shows the identical text to the paper.
SPCEO1 wrote: I saved that NASDAQ R&D Day presentation and it does include the picture with dimethyl glutaryl you mentioned. If you want a copy of the presentation, just e-mail me and I will send it along (rleonard@stewardhippartners.com).
jfm1330 wrote: I went back to the patent and they show molecular pictures of the curcumin PDC with both succinyl linker and dimethyl glutaryl linker. Also, at the end of the patent there is a list of key words from the patent, and sometimes with an image of a molecule. I found that both succinyl group dimethyl glutaryl group are there with a picture of each. So it is clear that they worked with both, but now I am no longer sure of which one is really used in TH1902. As I said, in a previous investor day presentation they showed a schematic picture of TH1902 with the dimethyl glutaryl linker. So either the investor day presentation was wrong, or there is a big mistake in their recent article.
https://patents.google.com/patent/WO2017088058A1/en
jfm1330 wrote: It was in the investor day pdf presentation that they showed that the linker was dimethyl glutarate. It was called DMG if I remember well. Unfortunately, this presentation is no longer on their website, the link is not working and I did not save a copy of it.
jfm1330 wrote: It seems to be the case, unless I totally missed something, but I don't think so. The thing is that it is likely to be much easier to link docetaxel to TH19P01 with succinic anhydride than to link it with dimethyl glutaric anhydride or with protected glutaric acid. So early on maybe they did it with succinic because it was easier and they did not need the selective cleavage attribute, and placed the wrong protocol in the article. I know it looks like chinese to a non chemist, but the succinic road is easy, while the dimethyl glutaric road is likely harder. Look at the two molecules, you will see similarities, but also the differences.
https://www.sigmaaldrich.com/CA/en/product/aldrich/239690
https://www.sigmaaldrich.com/CA/en/product/aldrich/d159808
SPCEO1 wrote: So, what is the implication of what you are saying - that the peer review process failed and there is something wrong with the article?
jfm1330 wrote: I started to read the article, but just at the chemistry section I was baffled. First they finally give the amino acids sequence of TH19P01 which is:
Acetyl-Gly-Val-Arg-Ala-Lys-Ala-Gly-Val-Arg-Asn-(Nle)-Phe-Lys-Ser-Glu-Ser-Tyr
So they have two lysines (Lys) strategically situated on both side of the peptide, with a nice gap in the middle. It's on these two lysines that the linker + docetaxel will be achored to the peptide. They have an acetyl group on the N-terminus of the peptide to give it more stability against enzymatic cleavage, they also have a norleucine (Nle) in the middle, which is probably a more stable (non sulfur) replacement for methionine.
That being said what I don't understand in the chemistry part is the linker. They use succinic anhydride to attach docetaxel to the lysines on the peptide, leaving a linker structure that is not what I saw in one of their previous presentation where they were claiming to use dimethyl glutaryl linker. And in the article, after descrbing the chemical reactions they end up with a molecule called TH19P01(SuDoce)2 or TH1902. So they claim there that the PDC with the succinyl linker is TH1902. It does not make sense because the succinyl linker is not cleavable under physilogic conditions. It is categorized as a non cleavable linker for ADCs. So I really don't understand why they claim that TH1902 has a succinyl linker, while before, they claimed it was dimethyl glutaryl.
https://www.selleckchem.com/products/succinic-anhydride.html