CLIPTAC Protein Degradation Technology Alternative Pre-Drug Design.

It's interesting to see a 2016 essay from Dr. Xie today.
this is an article published by Astex scientists in ACS Central Science (doi.org/10.1021/acscentsci.6b00280), which describes a protein degradation technique called CLIPTAC.
this technique combines PROTAC and dynamic combination chemistry to attach a trans-cyclic octene at the end of the target protein ligand and a tetrapyritosate at the end of the E3 nesase ligand.
the two compounds enter the cells and then click a chemical reaction to form a PROTAC molecule that degrades the target protein.
the authors validated the technique at the cellular level and proved that the PROTAC molecule could not enter the cell itself because the molecular weight was too large.
drug source analysis PROTAC and derivative technology is an important frontier in the development of small molecule drugs in the last 10 years, and this year's ASCO annual meeting will report the clinical data of the first PROTAC drug ARV101.
from the published summary, although the efficacy is general, but also found no unexpected side effects.
a long-distance attack new technology first kick door can do so has not been good, the industry can be from the target, link enzyme, to PROTAC design multi-angle optimization.
Roche today has just paid $135 million to develop a covalent ligand for the new E3 connective enzyme with Vividion.
The natural customers of E3 connecting enzymes are proteins, so the small molecular ligands of linked enzymes are not easy to find, the industry is still gnawing old VHL, Cereblon.
body has more than 600 E3 linked enzymes, so there is a lot of room for expansion.
the recent ENDTAC and LYTAC technologies are expected to solve the degradation of membrane proteins and free proteins, and may significantly expand the application range of protein degradation technology.
's article today is intended to address another difficulty in PROTAC technology, namely oral absorption and poor membrane resistance.
PROTAC is a dual-function molecule and is destined to have a large molecular weight, with about 1000 being very common.
link two ligands usually require some flexible, larger molecular fragments, which worsens the medicinal properties.
this CLIPTAC design utilizes a common click reaction in chemical biology, the so-called reverse electron demand Diels-Alder reaction between transene and tetraquin.
this reaction is similar to the classical click reaction that produces triazole, only the two functional groups can react efficiently, and there is no cross-reaction with other active groups, so the specificity is very high.
because PROTAC is divided in two, it is easier for each part to enter the cell.
enter the cells after the fire and dry wood form PROTAC, degradation of the target protein.
this idea is somewhat similar to the previous one called dynamic combination chemistry.
assume that the protein surface has two adjacent binding cavities, you can screen two fragments that bind to both binding chambers at the same time.
if the two fragments can be linked to a chemical reaction on the protein surface, a more active ligand can be found.
because free energy superposition slays can lead to exponential growth combined with constants, this strategy could theoretically be very effective, and this is the earliest idea based on fragment drug design."
but there are not many reversible reactions that can occur in aqueous solutions, so the technique is good-looking but doesn't really find anything high-quality pilots.
click chemistry because the structure is more complex and not suitable for the space of the same protein surface, so can not be used in this technology.
CLIPTAC is essentially a pre-drug design, it also faces the challenges of all pre-drug requirements.
a major problem is that if there is a reaction that doesn't arrive at the destination, the PROTAC is too big to get into the cells.
again, it's too slow to react to the destination, because both fragments are metabolized within a specified time, as all drugs do.
this requires that this chemical reaction occur at a sufficient rate in a room temperature neutral aqueous solution and at a nM concentration, which is a very strict requirement.
chemists (mainly Sharpless) were able to find a hand in thousands of chemical reactions that could count several so-called click chemical reactions.
Although these reactions can only be considered ugly ducklings in traditional organic synthesis, they play an indispensable role in modern biology research.
(formertitled: Alternative pre-drug CLIPTAC)