RE:RE:RE:RE:RE:RE:RE:Whats this? The paper is not wrong. From the patent, the wording looks identical. I think he jumped on one of the other linkers described in the patent and has been assuming that. What they have is cleaveable.
"Synthesis of Docetaxel-Katana peptide (KBA-106) conjugate DoceSuOH
1004221 DIEA (0.21 ml, 1.2 mmol) was added dropwise to a suspension of Docetaxel (0.81 g, 1.0 mmol) and succinic anhydride (105 mg, 1.05 mmol) in DMSO (5 ml) under stirring. The mixture was stirred at room temperature and monitored by UPLC-MS. After 2 h, the reaction was complete. The solvent was removed, and the resulting residue was dissolved in DCM and loaded on Biotage silica column for purification. DoceSuOH was obtained as a white powder after lyophilization, UPLC-MS purity > 95%. KBP106-(SuDoce)2 J004231 DIEA (0.234 mmol) was added dropwise to a solution of DoceSuOH (213 mg, 0.234 mmol) and TBTU (75 mg, 0.234 mmol) in DMSO (3-4 ml) in order to preactivate the DoceSuOH. The completion of preactivation was monitored by UPLC-MS, then a solution of KBP106 (120 mg, 0.062 mmol) in DMSO (0.2 ml) was added. The mixture was stirred at room temperature. The reaction was monitored by UPLC-MS until completion. The reaction mixture was purified using 3ORPC resin column and an AKTA purifier system (10% to 80% ACN) to give KBP106-(SuDoce)2 (145 mg) as white powder after lyophilization, UPLC-MS purity > 95%."
https://patents.google.com/patent/CA3071494A1/en
In that patent they also describe the expt from which they get the claim of bypassing MDR1. It seems like a good start for proving that claim, I'd like to see more though.
"In order to determine whether the anticancer drug-Katana-peptide conjugates could also be P-gp substrates, MDCK- transfected cells with human MDR1 were used (MDCK-MDR1). As shown in Fig. 6, the accumulation of the P-gp substrate [3H]-Docetaxel increased by 2-fold in the presence of cyclosporin A (CsA), a P-gp competitive inhibitor. However, the lack of CsA effect on the accumulation of [1251]-Docetaxel-Katana peptide conjugate indicates that upon its conjugation to KBP, the drug moiety is not recognized anymore by P-gp. The latter results confirm that Katana conjugates bypass efficiently the efflux action of P-gp.
J003911 In addition, the uptake of radiolabeled [1251]-Katana conjugate (KBA-105) was compared to that of unconjugated radiolabeled [3H]-Docetaxel in the ovarian cancer cells and in SKMEL-28 melanoma cancer cells in Fig. 7. Results demonstrate that the conjugate uptake in SKOV3 (Fig. 7A) as well as in SKMEL-28 cells (Fig. 7B) is faster and accumulates at higher concentrations than the unconjugated Docetaxel."
qwerty22 wrote:
No, as usual he jumped in with both feet, assumed something, it turns out he was wrong and now he's struggling to say "he was wrong". The usual MO. As it happens it looks like to me even in trying to understand it now he's still getting it wrong but my chemistry understanding is horrible.
Section 3.4
"The strategy for the conjugation of docetaxel to TH19P01 is described in the Methods section and schematized (Figure 5). In this strategy, a cleavable ester linker was used for conjugation of the docetaxel to the TH19P01."
Whatever he thinks it is it an ester linker that is cleavable by esterase enzymes inside the cell.
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