Are you familiar with PROTACs? If you are, please feel free to take a look at our PROTAC catalog. If you are not, then continue reading to learn more about PROTACs and how different linkers affect the efficacy and delivery to target molecules.
PROTACs, proteolysis targeting chimeras, are heterobifunctional small molecules composed of three distinct components: a warhead that binds to a target protein or protein of interest (POI), an anchor that binds to a E3 ubiquitin ligase, and a linker that conjugates the two ligands together (Figure 1). PROTACs take advantage of the ubiquitin-proteasome system (UPS), which is the waste disposal system of cells. This mechanism of PROTACs functions effectively at lower dosages, with reduced toxicity, and with prolonged pharmacodynamics when compared with more traditional inhibitors.
Figure
1: General structure of a PROTAC. The specific POI
targeting “warhead” (blue) is connected to the E3 ligase targeting “anchor”
(yellow) via a PROTAC linker.
It is becoming apparent
that the linker plays a critical role in the physicochemical properties and
bioactivity of the molecule. The length of the linker determines to what degree
the two ligands interact and thus the maximal activity of the PROTAC molecule. Cyrus' group determined that the optimal
linker length for estrogen receptor (ER)-alpha targeting PROTACS is 16 atoms
long. However, they also noted that the optimal distance between the two
ligands of any given PROTAC will need to be determined on a case-by-case basis.
There are a few common
chemical motifs that occur often in PROTAC linker design. These motifs were
recently highlighted by Maple's group in a database they compiled of
over 400 protein degrader structures. The most common motifs incorporated into
PROTAC linker structures are PEG, Alkyl, and other glycol chains of varying
lengths (Table 1).
Branched PEGs also
enable conjugations that produce compounds with multiple functionalities. For
example, research from Ma's group used a BroadPharm branched PEG to create a
dual-targeting molecule that increases the sensitivity of imaging for prostate
cancer. The current standard for prostate cancer screening involves the
determination of prostate-specific antigen (PSA) levels in patients' blood. The
problem with this method is high levels of PSA have been observed in benign
masses, and patients with low PSA still could have prostate metastases.
Another prostate cancer
biomarker, prostate-specific membrane antigen (PSMA), signifies the progression
of prostate cancer to androgen independence. PSMA has been gaining popularity
recently due to its potential in detecting metastasis of recurrent prostate
cancer. In order to improve the sensitivity and precision of prostate cancer
imaging, researchers sought to create a prostate cancer biomarker compound that
combined more than one biomarker. The BroadPharm branched PEG allowed
researchers to attach a PSA targeting moiety, a PSMA targeting moiety, and a
radiolabeling molecule together into one molecule (Figure 2). This dual
targeting approach not only increased the sensitivity of prostate cancer
diagnostics, it also laid the groundwork for a potential new treatment option
that would target cancer metastases once the compound was loaded with
therapeutic moieties.
Table 1: The
three most commonly occurring PROTAC linker motifs in Maple database.
(S,R.S)-AHPC-PEG linker
(Figure 3) is a PROTAC linker molecule that incorporates a von Hippel-Lindau
(VHL) E3 ligase ligand with a PEG linker. The VHL recruiting ligand is one of
the most widely used E3 ligands in PROTAC technology. The PEG spacer increases
reagent's solubility in aqueous media. This molecule allows for parallel synthesis
to be used to generate PROTAC libraries that feature variation in crosslinker
length, composition, and E3 ligase ligands due to the ability to select from
many different types of functional groups on the PEG linker.
Figure
2: Structure of (S,R.S)-AHPC-PEG linker can have
many different functional groups for bonding with POI ligands such as acid, amine, azide, alkyne, Tos, TCO, DBCO, etc.
The Pomaliodomide based
Cereblon (CRBN) ligand is another widely used E3 ligand. Two examples of CRBN
are Pomalidomide-PEG-Ph-NH2 (Figure 3, Left),
and Pomalidomide-PEG5-Azide (Figure 3,
Right). Pomalidomode-PEG-Ph-NH2 is a CRBN ligand and a 4-unit PEG linker with a
terminal amine. The amino group is reactive with carboxylic acids, activated
NHS esters, carbonyls (ketone, aldehyde) etc. Pomalidomide-PEG5-Azide is a CRBN
ligand and a 5-unit PEG linker with a terminal azide. The azide group on this
PROTAC technology enables click chemistry with alkyne, DBCO, and BCN molecules. This has been corroborated
by a high number of different synthetic approaches and provides a basis for
their importance in the future of PROTAC design.
As a worldwide leading
supplier of PROTAC Linkers and other biochemical
reagents, BroadPharm offers a wide variety of
compounds to empower our clients' advanced research and formulations.
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