Aishani Kumar, Thendral Yalini, Sunil Kumar C Science Reviews - Biology, 2024, 3(2), 1-12

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Unlocking Cellular Control: The Promise of PROTACs

in Disease Intervention

Aishani Kumar, Thendral Yalini, Sunil Kumar C

Affiliated with PES University, Bangalore, India; aishbijit@gmail.com, thendral2002@gmail.com, sunilkumarc@pes.edu

traditional approaches to medication development, offering a new idea that leverages the complexities of

biological mechanisms to accomplish highly focused degradation of particular proteins implicated in

pathological processes.[16] This novel strategy has the potential to address a number of drawbacks with

conventional therapy techniques, such as the development of drug resistance and unexpected adverse effects

resulting from interactions that are not intended. [14] The fundamental attraction of PROTACs is their distinct

mode of action, which is based on controlling the cell's own machinery for protein degradation.[11] This

orchestrated degradation translates to a substantial reduction in the levels of disease-driving proteins, often

leading to the disruption of critical pathways involved in cancer growth and progression.[9]

The in-depth principles underlying PROTAC technology are thoroughly explored in this review study, which

The methods used to create and refine PROTACs for various cancer types will be examined throughout the

review, along with the subtleties of the ligand and linker choices that are crucial to their effectiveness and

selectivity.[6] The difficulties and possibilities of transferring this ground-breaking technology from the lab to

clinical practice will also be thoroughly examined, with an emphasis on issues like bioavailability,

administration strategies, and potential resistance mechanisms.[9]

Through the integration of perspectives from various studies, the objective is to present a thorough but

succinct review of the state of ongoing PROTAC research, emphasizing both, noteworthy advancements and

the important issues that still need to be resolved. In the end, our investigation into PROTACs aims to shed

light on how they can change the face of cancer therapy by providing a preview of a day when targeted

protein degradation of disease-causing proteins would lead the way in novel therapeutic approaches.[9]

Millions of individuals worldwide are im-

pacted by the terrible disease known as cancer,

which not only has a detrimental effect on health

but also shortens life expectancy and causes death.

Thus, there is constant research and development

going on in the global health care system to find

new medicines and treatments or enhance those

Aishani Kumar, Thendral Yalini, Sunil Kumar C Science Reviews - Biology, 2024, 3(2), 1-12

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that already exist. In the field of cancer treatment,

numerous medicines and interventions have been

damages healthy cells as well, it frequently has se-

vere side effects such nausea, hair loss, and lowered

immunity. Radiation therapy can target malignant

tumors precisely, but it can additionally errone-

ously harm nearby normal cells, which can have ad-

verse effects over time.[5] By employing the body's

immune system, immunotherapy exhibits potential;

nevertheless, patient efficacy varies greatly, and im-

mune-related side effects are cause for concern. Spe-

cific molecular pathways are addressed by targeted

must carefully analyze the benefits and drawbacks

of each of these therapy options while taking the pa-

tient's features, cancer kind, and stage into account.

In order to combat this disease, a treatment where

the benefits greatly exceed the negatives and ad-

dress the shortcomings of the already available and

researched therapeutic techniques should be con-

sidered.[2][25]

system(UPS), to achieve highly specific and favora-

ble degradation of target proteins of interest impli-

cated in disease processes, particularly in cancer

therapy. [9] A PROTAC molecule is made up of

namely three components: a target POI, an appro-

priate ligand for an ubiquitin ligase (the enzyme

that attaches ubiquitin molecules to proteins), and a

linker unit that binds the two ligands. These factors

work together to speed up the degradation process.

A PROTAC-mediated protein degradation event

concurrently with the PROTAC's interaction with

an E3 ubiquitin ligase. The complex formed by the

cific amino acid residues on the protein target. This

is referred to as ubiquitination.[7]

Ubiquitination is the progressive attachment

resulting in a polymeric chain. This chain works as

a molecular indicator that proteasome, the cellular

machinery in charge of protein breakdown, recog-

nizes. Following that, the proteasome engages the

tagged target protein and commences its transloca-

critical pathways and functions associated with the

target protein, particularly in the context of cancer,

where the aberrant expression or activity of certain

proteins drives tumorigenesis.[11] The inherent se-

lectivity and specificity of PROTACs makes them

highly effective and appealing as a treatment

method. The choice of target protein ligand ensures

that the PROTAC binds with high affinity to the

specified target while sparing non-targeted pro-

teins.[7] Furthermore, the specificity of degradation

To summarize, PROTACs are a sophisticated

and novel approach to protein degradation that

uses the cell's natural protein turnover mechanism

to selectively and efficiently destroy disease-associ-

ated proteins. This mechanism of action has the po-

tential to transform cancer therapy and other fields

where precise regulation of protein levels is critical.

[4]

Parts of a PROTAC Molecule

Target-Binding Moiety: The fundamental ele-

ment in the architecture of Protac molecules is the

Science Reviews - Biology, 2024, 3(2), 1-12 Aishani Kumar, Thendral Yalini, Sunil Kumar C

specificity as well as high affinity. This component's

strategic selection is a critical factor of Protac per-

erties. Kinase inhibitors, hormone analogs, and cus-

tom ligands tailored for a specific POI are examples

of such moieties.[16]

Linker: Within the PROTAC structure, the

linker is an adjustable chemical conduit that con-

nects this target-binding segment to the E3 ligase-

recruiting moiety. It is critical in bringing the pro-

tein of choice and the E3 ubiquitin ligand close to

each other, aiding the process of ubiquitination and,

relationship between the constituent components,

and as such, they must be meticulously optimized.[3]

E3 Ligase-Recruiting Moiety: The E3 ligase-re-

cruiting moiety is the executive element in charge of

recruiting a specific E3 ubiquitin ligase, the key or-

chestrator of protein ubiquitination. This moiety is

often composed of a ligand or peptide fragment

with optimum binding affinity for the E3 ligase. The

meticulous selection of the E3 ligase recruiting moi-

[1]

Enhancements in Solubility and Cellular Per-

meability: In conjunction with the fundamental con-

stituents delineated previously, Protac molecules

commonly integrate modifications intended to im-

prove solubility and cellular permeability. This aug-

mentation aims to optimize their efficacy in both

cellular and in vivo environments. Such supple-

vailability, and intracellular uptake of the mole-

cule.[11]

PROTAC Delivery mechanisms

Nanoparticle mediated drug delivery has

been an impressive contender in the controlled re-

lease of therapeutic agents. The size of nanoparticles

perfect for nanomedical applications as the pre-

ferred range is below

200 nm. This range aids the drugs in diffusing into

The physicochemical and pharmacokinetic

properties of mesoporous silica nanoparticles have

been deeply investigated as drug nanocarriers.

They have many impressive properties such as me-

chanical, thermal and chemical stability. Their affin-

ity to adsorb many different types of molecules is

what gives them the incredible loading capacity in-

side the porous system. Drug delivery employing

nanosystems as well as nanosystems used for gene

Aishani Kumar, Thendral Yalini, Sunil Kumar C Science Reviews - Biology, 2024, 3(2), 1-12

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conventional treatments like radiation and chemo-

therapy, which leads to off-target effects and collat-

Overcoming Drug Resistance: It is commonly

known that cancer cells can develop resistance to

therapeutic medications, which over time can make

many treatments useless. By employing a novel

course of action, PROTACs might offer a work-

able resolution to this confusing circumstance.[13]

Because PROTACs promote the degradation of tar-

get proteins, they may be less susceptible to re-

sistance mechanisms than kinase inhibitors and

other small molecule inhibitors.[12]

target a wider variety of proteins, including those

with poorly defined binding pockets or druggable

sites, expanding the pool of possible therapeutic tar-

gets.[14]

Reduced Off-Target Effects: Arguably the

most important objective in cancer therapy is to re-

duce off-target effects, which frequently occur as a

side effect of treatment. By selectively attracting tar-

get proteins, PROTACs show promise in lowering

ibility of PROTACs allows them to be employed in

conjunction with a range of therapeutic modalities,

including immunotherapy, chemotherapy, and tar-

geted therapies. This provides access to synergistic

approaches that could enhance treatment effective-

ness while tackling cancer heterogeneity, which is

typically challenging to treat with single-agent ap-

proaches.[15]

Personalization Potential: A growing idea in

oncology is to customize cancer treatment to a pa-

In summary, PROTAC drugs offer ad-

vantages such tailored protein degradation, re-

sistance mitigation, increased target range, de-

creased off-target effects, synergy with combination

therapies, and personalization potential, hence pos-

ing an opportunity for new direction in cancer ther-

apy. Although additional research and clinical trials

are necessary to fully achieve the therapeutic poten-

tial of PROTACs, their unique mode of operation

renders them a desirable addition to the oncologist's

Prostate Cancer: The prostate, a tiny, walnut-

shaped organ in the male reproductive system, is

prone to cancer. Men with older age groups are

more likely to have it. Age, family history, and cer-

BRD4-binding component is linked to a ligand for

the Von Hippel-Lindau (VHL) protein by a linker.

This degrades BRD2/3/4 in CRPC (Castration-Re-

sistant Prostate Cancer) cell lines.

Science Reviews - Biology, 2024, 3(2), 1-12 Aishani Kumar, Thendral Yalini, Sunil Kumar C

Figure 1: ARV-771 [27]

Aishani Kumar, Thendral Yalini, Sunil Kumar C Science Reviews - Biology, 2024, 3(2), 1-12

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affects women, but also men, although less fre-

through the proteasome can be caused by