With the passage of time, PROTACs technology has entered an unprecedented stage of development in recent years. According to the different requirements of customers, BOC Sciences can design, synthesize, optimize PROTAC molecules, establish analytical methods and carry out the biological evaluation. Please visit https://protac.bocsci.com for more information.

1. PROTAC
Developing New Therapies Through Targeted
Protein Degradation

2. Background
01
Introduction
02
Development
03
Challenge
04
CONTENTS

3. Traditional drug research and development is
mainly focused on directly regulating the activity
of proteins or enzymes to treat diseases. The
development and application of protein activity
regulators, especially inhibitors, has always
been the mainstream direction of drug research
and development. Nucleic acid-based strategies
that control protein function by affecting protein
expression have recently made a breakthrough.
However, the poor metabolic stability and low
bioavailability limit the wide application of small
molecular nucleic acid technology.
Mechanism
PROTACs-induced targeted protein
degradation has emerged as a novel
therapeutic strategy in drug development.
Background

4. Protein degradation targeting chimera (PROTAC)
technology was derived from the Nobel Prize in the
category of Chemistry. On October 6, 2004, the
Royal Swedish Academy of Sciences announced
that the Nobel Prize in Chemistry would be awarded
to Israeli scientists Aaron Ciechanover, Avram
Hershko and American scientist Irwin Rose, for their
joint discovery of ubiquitin (Ub) regulated protein
degradation.
Background

5. PROTACs are heterobifunctional molecules, which
contain a small molecule targeting the protein of
interest (warhead), a small molecule capable of
recruiting an E3 ligase (E3 ligand), and a linker
connecting the above two moieties.
Introduction

6. The Ubiquitin itself consists of 76 amino acid residues
with a molecular weight of about 8.5 kDa. The name
"ubiquitin" is because it has a highly conserved
sequence and exists in all known eukaryotes. Ubiquitin
actually contains eight different amino acid residues
and can form complex polyubiquitin chains on the
target protein.
Ubiquitin and Ubiquitination
Ubiquitination refers to the process that ubiquitin
molecules classify intracellular proteins, select target
protein molecules, specifically modify target proteins and
form target protein polyubiquitin chains under the action of
a series of special enzymes. These special enzymes
include ubiquitin activating enzyme (E1), ubiquitin binding
enzyme (E2), ubiquitin ligase (E3) and so on.

7. Protacs achieve degradation through "hijacking" the cell's Ubiquitin–Proteosome system (UPS). The UPS
consists of an E1 activating enzyme which conjugates to an E2 enzyme transferring a ubiquitin molecule
to the E2. E2 then binds to the E3 ligase in a complex which can then recognize target proteins for
subsequent ubiquitin tagging and degradation by the 26S proteosome.
Mechanism
PROTACs-induced targeted protein
degradation has emerged as a novel
therapeutic strategy in drug development.
Mechanism

8. Traditional Drugs PROTAC Degraders
Active site required Active site not required
Transient and less durable Sustained degradation
Higher drug exposures required Lower doses for potent degradation
Strong binding required Weak binding is sufficient
Target of 1 function Target of all functions
Isoform non-specific lsoform specific
Inhibition of a subunit Degradation of a complex
Degradation vs Inhibition

9. Development

10. This PROTAC is composed of a short peptide that binds to E3 ubiquitin ligase and a small molecular that
binds to target protein, respectively, followed by polyubiquitination and proteasome degradation of target
Mechanism
PROTACs-induced targeted protein
degradation has emerged as a novel
therapeutic strategy in drug development.
PEPTIDE-BASED PROTAC TECHNOLOGY
DOI： 10.1002 / cbf.3369

11. This proteolysis targeting chimera (PROTAC) consists of a ligand on an E3 ubiquitin ligase, a linker, and a
ligand on targeted protein
Mechanism
PROTACs-induced targeted protein
degradation has emerged as a novel
therapeutic strategy in drug development.
Small molecule-BASED PROTAC TECHNOLOGY
DOI： 10.1002 / cbf.3369

12. Nuclear receptors
(ER, AR, RAR),
Protein kinases
(Akt, BCR-Abl, C-Abl, BTK, ALK,
CDK9,
RIPK2, DAPK1, PSD-95)
Proteins in transcriptional
regulation
(BRD4，Sirt2, HDAC6, TRIM24,
IKZF/3, Smad3)
Regulatory proteins
(CRABP-1/1, TACC3, AHR, FKBP12,
ERRa, X-protein)
Neuro-degenerative related proteins
(Huntingtin, Tau, a-synuclein, PSD-95)
Cellular metabolic enzymes
(MetAP-2, DHODH)
Fusion proteins
(Halo Tags)
Natural products:
(Estradiol, DHT, Apigenin.
ATRA.4-OHT, ovalicin)
Inhibitors:
(JQ1, OTX015, KHS101, AB3,
IACS-9571
thiazolidinedione,vandetanib
bosutinib,
dasatinib, ibrutinib, ceitinb,
azacarbazole)
Peptides
(QBP1, TH006)
SCFB-TRCP
VHL,
cIAP1
MDM2,
cereblon
APC/C,
Keap1
CMA
Peptides,
Pomalidomide,
Thalidomide,
Bestatin,
VHL1
Target proteins Ligand for targets
Ligand for E3 E3 ubiquitin ligase
Linker

15. The chart highlights the various steps involved from administration to intracellular degradation and the
biophysical techniques used to study them. In bold are common parameters to characterize PROTACs at
each stage.
The process of
PROTAC
development
Challenge

16. Traditional approaches
inefficient and prone to
artifacts
Rapid and faithful PROTAC
screening system not available
Only couple of ligases
are used as vehicle for
PROTACs
Many undruggable targets are
unPROTACtable due to lack of
ligases and rapid screening
Challenges with PROTAC
Miss toxicity and its detection,
especially long-term toxicity
and reproductive toxicity.

17. Key Questions To Consider When Developing Protein Degraders
PROTACs
Is my PROTAC
cell permeable?
Does my PROTAC form
a ternary complex
with
its target and the E3
recruiter?
Active E3 Complex
Does my target
become ubiquinated?
Is my target
recruited
to the proteasome?
Is my target
degraded?
UbiquitinTarget E3
Recruiter
E3

18. 01
03
05
02
04
06
Design of the
Ligase System
BOC Sciences's Complete Solution for PROTACs & Targeted Protein Degradation
Target Protein
Services
Structures and
Mechanisms of
PROTAC
PROTAC In Vivo
Evaluation
PROTAC Design
Services
PROTAC In Vitro
Evaluation

19. 01
03
05
02
04
06
E3 Ligase Ligand-Linker
Conjugate
BOC Sciences's PROTACs Related Products
Ligand for E3 Ligase
PROTAC
SNIPER
Ligand for Target Protein
PROTAC Linker
07
09
11
08
10
Ubiquitin Ligases Assay Kit
TargetsPROTAC in Vivo Evaluation
Molecular Glue

20. Our Advantages
Tech
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cal
supp
or
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Qual
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ranc
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ght
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ona
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Superior
after-sale
service
High-quality
one-stop
service
Extensive
experience
and
advanced
platforms
Custom assay design
to best fit your
project
A
variety
of
ligands
and
linkers
High efficient
data analytical
platform

21. Address: 45-16 Ramsey Road, Shirley, NY 11967, USA
Tel: 1-631-504-6093
Fax: 1-631-614-7828
E-Mail: protac@bocsci.com
Web: https://protac.bocsci.com/