Abstract

Targeted protein degradation (TPD) is a revolutionary approach to targeted therapy in hematological malignancies that potentially circumvents many constraints of existing small-molecule inhibitors. Heterobifunctional proteolysis-targeting chimeras (PROTACs) are the leading TPD drug class, with numerous agents now in clinical trials for a range of blood cancers. PROTACs harness the cell-intrinsic protein recycling infrastructure, the ubiquitin-proteasome system, to completely degrade target proteins. Distinct from targeted small-molecule inhibitor therapies, PROTACs can eliminate critical but conventionally “undruggable” targets, overcome resistance mechanisms to small-molecule therapies, and can improve tissue specificity and off-target toxicity. Orally bioavailable, PROTACs are not dependent on the occupancy-driven pharmacology inherent to inhibitory therapeutics, facilitating substoichiometric dosing that does not require an active or allosteric target binding site. Preliminary clinical data demonstrate promising therapeutic activity in heavily pretreated populations and novel technology platforms are poised to exploit a myriad of permutations of PROTAC molecular design to enhance efficacy and targeting specificity. As the field rapidly progresses and various non-PROTAC TPD drug candidates emerge, this review explores the scientific and preclinical foundations of PROTACs and presents them within common clinical contexts. Additionally, we examine the latest findings from ongoing active PROTAC clinical trials.

1.
Harrison
RK
.
Phase II and phase III failures: 2013-2015
.
Nat Rev Drug Discov
.
2016
;
15
(
12
):
817
-
818
.
2.
Kiriiri
GK
,
Njogu
PM
,
Mwangi
AN
.
Exploring different approaches to improve the success of drug discovery and development projects: a review
.
Futur J Pharm Sci
.
2020
;
6
(
1
):
27
.
3.
Hinkson
IV
,
Madej
B
,
Stahlberg
EA
.
Accelerating therapeutics for opportunities in medicine: a paradigm shift in drug discovery
.
Front Pharmacol
.
2020
;
11
:
770
.
4.
Dowden
H
,
Munro
J
.
Trends in clinical success rates and therapeutic focus
.
Nat Rev Drug Discov
.
2019
;
18
(
7
):
495
-
496
.
5.
Neklesa
TK
,
Winkler
JD
,
Crews
CM
.
Targeted protein degradation by PROTACs
.
Pharmacol Ther
.
2017
;
174
:
138
-
144
.
6.
Olsen
SK
,
Lima
CD
.
Structure of a ubiquitin E1-E2 complex: insights to E1-E2 thioester transfer
.
Mol Cell
.
2013
;
49
(
5
):
884
-
896
.
7.
Lee
I
,
Schindelin
H
.
Structural insights into E1-catalyzed ubiquitin activation and transfer to conjugating enzymes
.
Cell
.
2008
;
134
(
2
):
268
-
278
.
8.
DeMartino
GN
,
Slaughter
CA
.
The proteasome, a novel protease regulated by multiple mechanisms
.
J Biol Chem
.
1999
;
274
(
32
):
22123
-
22126
.
9.
Verma
R
,
Oania
R
,
Graumann
J
,
Deshaies
RJ
.
Multiubiquitin chain receptors define a layer of substrate selectivity in the ubiquitin-proteasome system
.
Cell
.
2004
;
118
(
1
):
99
-
110
.
10.
Yao
T
,
Cohen
RE
.
A cryptic protease couples deubiquitination and degradation by the proteasome
.
Nature
.
2002
;
419
(
6905
):
403
-
407
.
11.
Deshaies
RJ
,
Joazeiro
CAP
.
RING domain E3 ubiquitin ligases
.
Annu Rev Biochem
.
2009
;
78
(
1
):
399
-
434
.
12.
Abbas
R
,
Larisch
S
.
Killing by degradation: regulation of apoptosis by the ubiquitin-proteasome-system
.
Cells
.
2021
;
10
(
12
):
3465
.
13.
Kleiger
G
,
Mayor
T
.
Perilous journey: a tour of the ubiquitin–proteasome system
.
Trends Cell Biol
.
2014
;
24
(
6
):
352
-
359
.
14.
Sakamoto
KM
,
Kim
KB
,
Kumagai
A
,
Mercurio
F
,
Crews
CM
,
Deshaies
RJ
.
Protacs: chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation
.
Proc National Acad Sci
.
2001
;
98
(
15
):
8554
-
8559
.
15.
Sakamoto
KM
,
Kim
KB
,
Verma
R
, et al
.
Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation
.
Mol Cell Proteomics
.
2003
;
2
(
12
):
1350
-
1358
.
16.
Schneekloth
AR
,
Pucheault
M
,
Tae
HS
,
Crews
CM
.
Targeted intracellular protein degradation induced by a small molecule: en route to chemical proteomics
.
Bioorg Med Chem Lett
.
2008
;
18
(
22
):
5904
-
5908
.
17.
Ito
T
,
Ando
H
,
Suzuki
T
, et al
.
Identification of a primary target of thalidomide teratogenicity
.
Science
.
2010
;
327
(
5971
):
1345
-
1350
.
18.
Gadd
MS
,
Testa
A
,
Lucas
X
, et al
.
Structural basis of PROTAC cooperative recognition for selective protein degradation
.
Nat Chem Biol
.
2017
;
13
(
5
):
514
-
521
.
19.
Luo
X
,
Archibeque
I
,
Dellamaggiore
K
, et al
.
Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases
.
Iscience
.
2022
;
25
(
3
):
103985
.
20.
Khan
S
,
Zhang
X
,
Lv
D
, et al
.
A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity
.
Nat Med
.
2019
;
25
(
12
):
1938
-
1947
.
21.
Ahmad
G
,
Mohapatra
BC
,
Schulte
NA
, et al
.
Cbl-family ubiquitin ligases and their recruitment of CIN85 are largely dispensable for epidermal growth factor receptor endocytosis
.
Int J Biochem Cell Biol
.
2014
;
57
:
123
-
134
.
22.
Wade
M
,
Wahl
GM
.
Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry?
.
Mol Cancer Res
.
2009
;
7
(
1
):
1
-
11
.
23.
Békés
M
,
Langley
DR
,
Crews
CM
.
PROTAC targeted protein degraders: the past is prologue
.
Nat Rev Drug Discov
.
2022
;
21
(
3
):
181
-
200
.
24.
Belcher
BP
,
Ward
CC
,
Nomura
DK
.
Ligandability of E3 ligases for targeted protein degradation applications
.
Biochemistry-us
.
2023
;
62
(
3
):
588
-
600
.
25.
Boike
L
,
Henning
NJ
,
Nomura
DK
.
Advances in covalent drug discovery
.
Nat Rev Drug Discov
.
2022
;
21
(
12
):
881
-
898
.
26.
Zhang
QC
,
Petrey
D
,
Deng
L
, et al
.
Structure-based prediction of protein–protein interactions on a genome-wide scale
.
Nature
.
2012
;
490
(
7421
):
556
-
560
.
27.
Bricelj
A
,
Steinebach
C
,
Kuchta
R
,
Gütschow
M
,
Sosič
I
.
E3 ligase ligands in successful PROTACs: an overview of syntheses and linker attachment points
.
Front Chem
.
2021
;
9
:
707317
.
28.
Nowak
RP
,
DeAngelo
SL
,
Buckley
D
, et al
.
Plasticity in binding confers selectivity in ligand-induced protein degradation
.
Nat Chem Biol
.
2018
;
14
(
7
):
706
-
714
.
29.
Bemis
TA
,
La Clair
JJ
,
Burkart
MD
.
Unraveling the role of linker design in proteolysis targeting chimeras
.
J Med Chem
.
2021
;
64
(
12
):
8042
-
8052
.
30.
Smith
BE
,
Wang
SL
,
Jaime-Figueroa
S
, et al
.
Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase
.
Nat Commun
.
2019
;
10
(
1
):
131
.
31.
Bricelj
A
,
Dora Ng
YL
,
Ferber
D
, et al
.
Influence of linker attachment points on the stability and neosubstrate degradation of cereblon ligands
.
ACS Med Chem Lett
.
2021
;
12
(
11
):
1733
-
1738
.
32.
Schiemer
J
,
Horst
R
,
Meng
Y
, et al
.
Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes
.
Nat Chem Biol
.
2021
;
17
(
2
):
152
-
160
.
33.
Atilaw
Y
,
Poongavanam
V
,
Svensson Nilsson
C
, et al
.
Solution conformations shed light on PROTAC cell permeability
.
ACS Med Chem Lett
.
2021
;
12
(
1
):
107
-
114
.
34.
Goodnow
RA
,
Dumelin
CE
,
Keefe
AD
.
DNA-encoded chemistry: enabling the deeper sampling of chemical space
.
Nat Rev Drug Discov
.
2017
;
16
(
2
):
131
-
147
.
35.
Disch
JS
,
Duffy
JM
,
Lee
ECY
, et al
.
Bispecific estrogen receptor α degraders incorporating novel binders identified using DNA-encoded chemical library screening
.
J Med Chem
.
2021
;
64
(
8
):
5049
-
5066
.
36.
Ishida
T
,
Ciulli
A
.
E3 ligase ligands for PROTACs: how they were found and how to discover new ones
.
Slas Discov
.
2021
;
26
(
4
):
484
-
502
.
37.
Chen
Q
,
Liu
C
,
Wang
W
, et al
.
Optimization of PROTAC ternary complex using DNA encoded library approach
.
ACS Chem Biol
.
2023
;
18
(
1
):
25
-
33
.
38.
Sunkari
YK
,
Siripuram
VK
,
Nguyen
T-L
,
Flajolet
M
.
High-power screening (HPS) empowered by DNA-encoded libraries
.
Trends Pharmacol Sci
.
2022
;
43
(
1
):
4
-
15
.
39.
Adjei
AA
.
What is the right dose? The elusive optimal biologic dose in phase I clinical trials
.
J Clin Oncol
.
2006
;
24
(
25
):
4054
-
4055
.
40.
Han
X
,
Zhao
L
,
Xiang
W
, et al
.
Discovery of highly potent and efficient PROTAC degraders of androgen receptor (AR) by employing weak binding affinity VHL E3 ligase ligands
.
J Med Chem
.
2019
;
62
(
24
):
11218
-
11231
.
41.
Bondeson
DP
,
Smith
BE
,
Burslem
GM
, et al
.
Lessons in PROTAC design from selective degradation with a promiscuous warhead
.
Cell Chem Biol
.
2018
;
25
(
1
):
78
-
87.e5
.
42.
Gechijian
LN
,
Buckley
DL
,
Lawlor
MA
, et al
.
Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands
.
Nat Chem Biol
.
2018
;
14
(
4
):
405
-
412
.
43.
Huang
H-T
,
Dobrovolsky
D
,
Paulk
J
, et al
.
A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader
.
Cell Chem Biol
.
2018
;
25
(
1
):
88
-
99.e6
.
44.
Zorba
A
,
Nguyen
C
,
Xu
Y
, et al
.
Delineating the role of cooperativity in the design of potent PROTACs for BTK
.
Proc Natl Acad Sci U S A
.
2018
;
115
(
31
):
E7285
-
E7292
.
45.
Buckley
DL
,
Gustafson
JL
,
Van Molle
I
, et al
.
Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α
.
Angew Chem Int Ed
.
2012
;
51
(
46
):
11463
-
11467
.
46.
Galdeano
C
,
Gadd
MS
,
Soares
P
, et al
.
Structure-guided design and optimization of small molecules targeting the protein–protein interaction between the von Hippel–Lindau (VHL) E3 ubiquitin ligase and the Hypoxia Inducible Factor (HIF) alpha subunit with in vitro nanomolar affinities
.
J Med Chem
.
2014
;
57
(
20
):
8657
-
8663
.
47.
Zengerle
M
,
Chan
K-H
,
Ciulli
A
.
Selective small molecule induced degradation of the BET bromodomain protein BRD4
.
ACS Chem Biol
.
2015
;
10
(
8
):
1770
-
1777
.
48.
Tovell
H
,
Testa
A
,
Zhou
H
, et al
.
Design and characterization of SGK3-PROTAC1, an isoform specific SGK3 kinase PROTAC degrader
.
ACS Chem Biol
.
2019
;
14
(
9
):
2024
-
2034
.
49.
Douglass
EF
,
Miller
CJ
,
Sparer
G
,
Shapiro
H
,
Spiegel
DA
.
A comprehensive mathematical model for three-body binding equilibria
.
J Am Chem Soc
.
2013
;
135
(
16
):
6092
-
6099
.
50.
Chamberlain
PP
,
Hamann
LG
.
Development of targeted protein degradation therapeutics
.
Nat Chem Biol
.
2019
;
15
(
10
):
937
-
944
.
51.
Buckley
DL
,
Raina
K
,
Darricarrere
N
, et al
.
HaloPROTACS: use of small molecule PROTACs to induce degradation of HaloTag fusion proteins
.
ACS Chem Biol
.
2015
;
10
(
8
):
1831
-
1837
.
52.
Riching
KM
,
Caine
EA
,
Urh
M
,
Daniels
DL
.
The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation
.
Chem Soc Rev
.
2022
;
51
(
14
):
6210
-
6221
.
53.
Pettersson
M
,
Crews
CM
.
PROteolysis TArgeting Chimeras (PROTACs) — past, present and future
.
Drug Discov Today Technol
.
2019
;
31
:
15
-
27
.
54.
Poongavanam
V
,
Kihlberg
J
.
PROTAC cell permeability and oral bioavailability: a journey into uncharted territory
.
Future Med Chem
.
2022
;
14
(
3
):
123
-
126
.
55.
Lipinski
CA
,
Lombardo
F
,
Dominy
BW
,
Feeney
PJ
.
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
.
Adv Drug Deliv Rev
.
1997
;
23
(
1–3
):
3
-
25
.
56.
Cecchini
C
,
Pannilunghi
S
,
Tardy
S
,
Scapozza
L
.
From conception to development: investigating PROTACs features for improved cell permeability and successful protein degradation
.
Front Chem
.
2021
;
9
:
672267
.
57.
Lai
AC
,
Toure
M
,
Hellerschmied
D
, et al
.
Modular PROTAC design for the degradation of oncogenic BCR-ABL
.
Angew Chem Int Ed
.
2016
;
55
(
2
):
807
-
810
.
58.
Jiang
B
,
Wang
ES
,
Donovan
KA
, et al
.
Development of dual and selective degraders of cyclin-dependent kinases 4 and 6
.
Angew Chem Int Ed
.
2019
;
58
(
19
):
6321
-
6326
.
59.
Yamanaka
S
,
Furihata
H
,
Yanagihara
Y
, et al
.
Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation
.
Nat Commun
.
2023
;
14
(
1
):
4683
.
60.
Ignatov
M
,
Jindal
A
,
Kotelnikov
S
, et al
.
High accuracy prediction of PROTAC complex structures
.
J Am Chem Soc
.
2023
;
145
(
13
):
7123
-
7135
.
61.
Nowak
RP
,
Jones
LH
.
Target validation using PROTACs: applying the four pillars framework
.
SLAS Discov
.
2021
;
26
(
4
):
474
-
483
.
62.
Li
Z
,
Van Calcar
S
,
Qu
C
,
Cavenee
WK
,
Zhang
MQ
,
Ren
B
.
A global transcriptional regulatory role for c-Myc in Burkitt’s lymphoma cells
.
Proc Natl Acad Sci U S A
.
2003
;
100
(
14
):
8164
-
8169
.
63.
Fernandez
PC
,
Frank
SR
,
Wang
L
, et al
.
Genomic targets of the human c-Myc protein
.
Genes Dev
.
2003
;
17
(
9
):
1115
-
1129
.
64.
Schick
M
,
Habringer
S
,
Nilsson
JA
,
Keller
U
.
Pathogenesis and therapeutic targeting of aberrant MYC expression in haematological cancers
.
Br J Haematol
.
2017
;
179
(
5
):
724
-
738
.
65.
Felsher
DW
.
MYC inactivation elicits oncogene addiction through both tumor cell–intrinsic and host-dependent mechanisms
.
Genes Cancer
.
2010
;
1
(
6
):
597
-
604
.
66.
Jain
M
,
Arvanitis
C
,
Chu
K
, et al
.
Sustained loss of a neoplastic phenotype by brief inactivation of MYC
.
Science
.
2002
;
297
(
5578
):
102
-
104
.
67.
Fukazawa
T
,
Maeda
Y
,
Matsuoka
J
, et al
.
Inhibition of Myc effectively targets KRAS mutation-positive lung cancer expressing high levels of Myc
.
Anticancer Res
.
2010
;
30
(
10
):
4193
-
4200
.
68.
Llombart
V
,
Mansour
MR
.
Therapeutic targeting of “undruggable” MYC
.
EBioMedicine
.
2022
;
75
:
103756
.
69.
Nishida
Y
,
Ayoub
E
,
Scruggs
D
, et al
.
Stem-cell enriched cellular hierarchy of TP53 mutant acute myeloid leukemia is vulnerable to targeted protein degradation of c-MYC [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
583
.
70.
Munir
F
,
Khazaei
S
,
Calkins
PH
, et al
.
Targeted protein degradation for c-MYC overcomes therapy resistance in T-cell acute lymphoblastic leukemias [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
1447
.
71.
Dawson
MA
,
Prinjha
RK
,
Dittmann
A
, et al
.
Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia
.
Nature
.
2011
;
478
(
7370
):
529
-
533
.
72.
Lu
J
,
Qian
Y
,
Altieri
M
, et al
.
Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4
.
Chem Biol
.
2015
;
22
(
6
):
755
-
763
.
73.
Ma
L
,
Wang
J
,
Zhang
Y
, et al
.
BRD4 PROTAC degrader MZ1 exerts anticancer effects in acute myeloid leukemia by targeting c-Myc and ANP32B genes
.
Cancer Biol Ther
.
2022
;
23
(
1
):
1
-
15
.
74.
Zhang
K
,
Gao
L
,
Wang
J
, et al
.
A novel BRD family PROTAC inhibitor dBET1 exerts great anti-cancer effects by targeting c-MYC in acute myeloid leukemia cells
.
Pathol Oncol Res
.
2022
;
28
:
1610447
.
75.
Qin
C
,
Hu
Y
,
Zhou
B
, et al
.
Discovery of QCA570 as an exceptionally potent and efficacious proteolysis targeting chimera (PROTAC) degrader of the bromodomain and extra-terminal (BET) proteins capable of inducing complete and durable tumor regression
.
J Med Chem
.
2018
;
61
(
15
):
6685
-
6704
.
76.
Piya
S
,
Mu
H
,
Bhattacharya
S
, et al
.
BETP degradation simultaneously targets acute myelogenous leukemia stem cells and the microenvironment
.
J Clin Invest
.
2019
;
129
(
5
):
1878
-
1894
.
77.
Furukawa
K
,
Shimada
K
,
Esaki
M
, et al
.
Development and efficacy of a novel bromodomain and extraterminal domain degrader K-256 in MYC/BCL2-related lymphoma [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
5008
.
78.
Johnson
DE
,
O’Keefe
RA
,
Grandis
JR
.
Targeting the IL-6/JAK/STAT3 signalling axis in cancer
.
Nat Rev Clin Oncol
.
2018
;
15
(
4
):
234
-
248
.
79.
Frank
DA
.
STAT3 as a central mediator of neoplastic cellular transformation
.
Cancer Lett
.
2007
;
251
(
2
):
199
-
210
.
80.
Yu
H
,
Kortylewski
M
,
Pardoll
D
.
Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment
.
Nat Rev Immunol
.
2007
;
7
(
1
):
41
-
51
.
81.
Lee
H-J
,
Zhuang
G
,
Cao
Y
,
Du
P
,
Kim
HJ
,
Settleman
J
.
Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells
.
Cancer Cell
.
2014
;
26
(
2
):
207
-
221
.
82.
Levy
DE
,
Darnell
JE
.
STATs: transcriptional control and biological impact
.
Nat Rev Mol Cell Biol
.
2002
;
3
(
9
):
651
-
662
.
83.
Beebe
JD
,
Liu
J-Y
,
Zhang
J-T
.
Two decades of research in discovery of anticancer drugs targeting STAT3, how close are we?
.
Pharmacol Ther
.
2018
;
191
:
74
-
91
.
84.
Yang
J
,
Stark
GR
.
Roles of unphosphorylated STATs in signaling
.
Cell Res
.
2008
;
18
(
4
):
443
-
451
.
85.
Bai
L
,
Zhou
H
,
Xu
R
, et al
.
A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo
.
Cancer Cell
.
2019
;
36
(
5
):
498
-
511.e17
.
86.
Zhou
H
,
Bai
L
,
Xu
R
, et al
.
SD-91 as a potent and selective STAT3 degrader capable of achieving complete and long-lasting tumor regression
.
ACS Med Chem Lett
.
2021
;
12
(
6
):
996
-
1004
.
87.
Liu
PC
,
Dixit
V
,
Mayo
M
, et al
.
A first-in-class STAT3 degrader KT-333 in development for treatment of hematologic cancers [abstract]
.
Blood
.
2021
;
138
(
suppl 1
):
1865
.
88.
Danilov
A
,
Tees
MT
,
Patel
K
, et al
.
A first-in-human phase 1 trial of NX-2127, a first-in-class Bruton’s tyrosine kinase (BTK) dual-targeted protein degrader with immunomodulatory activity, in patients with relapsed/refractory B cell malignancies [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
4463
.
89.
Searle
E
,
Forconi
F
,
Linton
K
, et al
.
Initial findings from a first-in-human phase 1a/b trial of NX-5948, a selective Bruton’s tyrosine kinase (BTK) degrader, in patients with relapsed/refractory B cell malignancies [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
4473
.
90.
Seymour
JF
,
Cheah
CY
,
Parrondo
R
, et al
.
First results from a phase 1, first-in-human study of the Bruton’s tyrosine kinase (BTK) degrader Bgb-16673 in patients (Pts) with relapsed or refractory (R/R) B-cell malignancies (BGB-16673-101) [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
4401
.
91.
Li
J
,
Xu
W
,
Yan
P
,
Cao
Y
,
Hu
M
,
Daley
W
.
Abstract CT128: phase 1 study of HSK29116, a Bruton tyrosine kinase (BTK) proteolysis-targeting chimera (PROTAC) agent, in patients with relapsed or refractory B-cell malignancies
.
Cancer Res
.
2023
;
83
(
8 suppl
):
CT128
.
92.
Accutar Biotech Pipeline
.
Latest progress of our drug discovery programs
. Accessed 13 September 2023. https://www.accutarbio.com/workflow/.
93.
AbbVie Pipeline
.
Advanced medicines that demonstrate both strong clinical performance and benefits to patients
. Accessed 1 November 2023. https://www.abbvie.com/science/pipeline.html.
94.
Shastri
A
,
Feldman
EJ
,
Starodub
AN
, et al
.
Preliminary safety, pharmacokinetics, pharmacodynamics and clinical activity of KT-333, a targeted protein degrader of STAT3, in patients with relapsed or refractory lymphomas, large granular lymphocytic leukemia, and solid tumors [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
3081
.
95.
Lue
JK
,
Stevens
DA
,
Williams
ME
, et al
.
Phase 1 study of KT-413, a targeted protein degrader of IRAK4 and IMiD substrates, in adult patients with relapsed or refractory B-cell non-Hodgkin lymphoma [abstract]
.
Blood
.
2022
;
140
(
suppl 1
):
12143
-
12144
.
96.
He
Y
,
Koch
R
,
Budamagunta
V
, et al
.
DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas
.
J Hematol Oncol
.
2020
;
13
(
1
):
95
.
97.
Foley
K
,
Dai
Y
,
Ding
Q
, et al
.
Tumor-selective, chaperone-mediated protein degradation (CHAMP) of the bromodomain transcription factor BRD4 [abstract]
.
Eur J Cancer
.
2022
;
174
:
S27
.
98.
Burger
JA
,
Wiestner
A
.
Targeting B cell receptor signalling in cancer: preclinical and clinical advances
.
Nat Rev Cancer
.
2018
;
18
(
3
):
148
-
167
.
99.
Vetrie
D
.
The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases
.
Nature
.
1993
;
364
(
6435
):
362
.
100.
Pal Singh
S
,
Dammeijer
F
,
Hendriks
RW
.
Role of Bruton’s tyrosine kinase in B cells and malignancies
.
Mol Cancer
.
2018
;
17
(
1
):
57
.
101.
Woyach
JA
,
Furman
RR
,
Liu
TM
, et al
.
Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib
.
N Engl J Med
.
2014
;
370
(
24
):
2286
-
2294
.
102.
Wang
E
,
Mi
X
,
Thompson
MC
, et al
.
Mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors
.
N Engl J Med
.
2022
;
386
(
8
):
735
-
743
.
103.
Lampson
BL
,
Brown
JR
.
Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?
.
Expert Rev Hematol
.
2018
;
11
(
3
):
185
-
194
.
104.
Aslan
B
,
Kismali
G
,
Iles
LR
, et al
.
Pirtobrutinib inhibits wild-type and mutant Bruton’s tyrosine kinase-mediated signaling in chronic lymphocytic leukemia
.
Blood Cancer J
.
2022
;
12
(
5
):
80
.
105.
Mato
AR
,
Shah
NN
,
Jurczak
W
, et al
.
Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study
.
Lancet
.
2021
;
397
(
10277
):
892
-
901
.
106.
Naeem
A
,
Utro
F
,
Wang
Q
, et al
.
Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance
.
Blood Adv
.
2023
;
7
(
9
):
1929
-
1943
.
107.
Blombery
P
,
Thompson
ER
,
Lew
TE
, et al
.
Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross resistance
.
Blood Adv
.
2022
;
6
(
20
):
5589
-
5592
.
108.
Noviski
MA
,
Ma
J
,
Lee
E
, et al
.
Abstract 1126: concurrent degradation of BTK and IMiD neosubstrates by NX-2127 enhances multiple mechanisms of tumor killing
.
Cancer Res
.
2022
;
82
(
suppl 12
):
1126
.
109.
Montoya
S
,
Bourcier
J
,
Thompson
MC
, et al
.
Kinase dead BTK mutations confer resistance to covalent and noncovalent BTK inhibitors but are susceptible to clinical stage BTK degraders [abstract]
.
Blood
.
2022
;
140
(
suppl 1
):
1811
-
1813
.
110.
Mato
AR
,
Wierda
WG
,
Ai
WZ
, et al
.
NX-2127-001, a first-in-human trial of NX-2127, a Bruton’s tyrosine kinase-targeted protein degrader, in patients with relapsed or refractory chronic lymphocytic leukemia and B-cell malignancies [abstract]
.
Blood
.
2022
;
140
(
suppl 1
):
2329
-
2332
.
111.
Mato
A
,
Danilov
A
,
Patel
MR
, et al
.
P649: a first-in-human phase 1 trial of NX-2127, a first-in-class oral BTK degrader with IMID-like activity, in patients with relapsed and refractory B-cell malignancies [abstract]
.
Hemasphere
.
2022
;
6
:
547
-
548
.
112.
Robbins
DW
,
Noviski
M
,
Rountree
R
, et al
.
Nx-5948, a selective degrader of BTK with activity in preclinical models of hematologic and brain malignancies [abstract]
.
Blood
.
2021
;
138
(
suppl 1
):
2251
.
113.
Feng
X
,
Wang
Y
,
Long
T
, et al
.
P1239: Bruton tyrosine kinase (BTK) protein degrader BGB-16673 is less APT to cause, and able to overcome variable BTK resistance mutations compared to other BTK inhibitors (BTKI)
.
HemaSphere
.
2023
;
7
(
S3
):
e368855c
.
114.
Lee
T
,
Potts
SJ
,
Kantarjian
H
,
Cortes
J
,
Giles
F
,
Albitar
M
.
Molecular basis explanation for imatinib resistance of BCR-ABL due to T315I and P-loop mutations from molecular dynamics simulations
.
Cancer
.
2008
;
112
(
8
):
1744
-
1753
.
115.
Cortes
J
,
Lang
F
.
Third-line therapy for chronic myeloid leukemia: current status and future directions
.
J Hematol Oncol
.
2021
;
14
(
1
):
44
.
116.
Yang
Y
,
Gao
H
,
Sun
X
, et al
.
Global PROTAC toolbox for degrading BCR–ABL overcomes drug-resistant mutants and adverse effects
.
J Med Chem
.
2020
;
63
(
15
):
8567
-
8583
.
117.
Ma
B
,
Feng
H
,
Feng
C
, et al
.
Kill two birds with one stone: a multifunctional dual-targeting protein drug to overcome imatinib resistance in Philadelphia chromosome-positive leukemia
.
Adv Sci
.
2022
;
9
(
13
):
2104850
.
118.
Rouhimoghadam
M
,
Tang
H
,
Liao
J
, et al
.
LPA81: discovery of an exceptionally potent Protac degrading native and mutant BCR-ABL1 oncoprotein in CML [abstract]
.
Blood
.
2022
;
140
(
suppl 1
):
485
-
486
.
119.
Hanahan
D
,
Weinberg
RA
.
Hallmarks of cancer: the next generation
.
Cell
.
2011
;
144
(
5
):
646
-
674
.
120.
Zaman
S
,
Wang
R
,
Gandhi
V
.
Targeting the apoptosis pathway in hematologic malignancies
.
Leuk Lymphoma
.
2014
;
55
(
9
):
1980
-
1992
.
121.
Bannerji
R
,
Kitada
S
,
Flinn
IW
, et al
.
Apoptotic-regulatory and complement-protecting protein expression in chronic lymphocytic leukemia: relationship to in vivo rituximab resistance
.
J Clin Oncol
.
2003
;
21
(
8
):
1466
-
1471
.
122.
Tse
C
,
Shoemaker
AR
,
Adickes
J
, et al
.
ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor
.
Cancer Res
.
2008
;
68
(
9
):
3421
-
3428
.
123.
Roberts
AW
,
Seymour
JF
,
Brown
JR
, et al
.
Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease
.
J Clin Oncol
.
2012
;
30
(
5
):
488
-
496
.
124.
Wilson
WH
,
O’Connor
OA
,
Czuczman
MS
, et al
.
Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity
.
Lancet Oncol
.
2010
;
11
(
12
):
1149
-
1159
.
125.
Schoenwaelder
SM
,
Jarman
KE
,
Gardiner
EE
, et al
.
Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets
.
Blood
.
2011
;
118
(
6
):
1663
-
1674
.
126.
He
Y
,
Zhang
X
,
Chang
J
, et al
.
Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity
.
Nat Commun
.
2020
;
11
(
1
):
1996
.
127.
Ottis
P
,
Palladino
C
,
Thienger
P
, et al
.
Cellular resistance mechanisms to targeted protein degradation converge toward impairment of the engaged ubiquitin transfer pathway
.
ACS Chem Biol
.
2019
;
14
(
10
):
2215
-
2223
.
128.
Zhang
L
,
Riley-Gillis
B
,
Vijay
P
,
Shen
Y
.
Acquired resistance to BET-PROTACs (Proteolysis-Targeting Chimeras) caused by genomic alterations in core components of E3 ligase complexes
.
Mol Cancer Ther
.
2019
;
18
(
7
):
1302
-
1311
.
129.
Shirasaki
R
,
Matthews
GM
,
Gandolfi
S
, et al
.
Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins
.
Cell Rep
.
2021
;
34
(
1
):
108532
.
130.
Jiang
B
,
Gao
Y
,
Che
J
, et al
.
Discovery and resistance mechanism of a selective CDK12 degrader
.
Nat Chem Biol
.
2021
;
17
(
6
):
675
-
683
.
131.
Kurimchak
AM
,
Herrera-Montávez
C
,
Montserrat-Sangrà
S
, et al
.
The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells
.
Sci Signal
.
2022
;
15
(
749
):
eabn2707
.
132.
Cotton
AD
,
Nguyen
DP
,
Gramespacher
JA
,
Seiple
IB
,
Wells
JA
.
Development of antibody-based PROTACs for the degradation of the cell-surface immune checkpoint protein PD-L1
.
J Am Chem Soc
.
2021
;
143
(
2
):
593
-
598
.
133.
Shih
P-C
,
Naganuma
M
,
Demizu
Y
,
Naito
M
.
Current status of oligonucleotide-based protein degraders
.
Pharmaceutics
.
2023
;
15
(
3
):
765
.
134.
Roberts
TC
,
Langer
R
,
Wood
MJA
.
Advances in oligonucleotide drug delivery
.
Nat Rev Drug Discov
.
2020
;
19
(
10
):
673
-
694
.
135.
Imaide
S
,
Riching
KM
,
Makukhin
N
, et al
.
Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity
.
Nat Chem Biol
.
2021
;
17
(
11
):
1157
-
1167
.
136.
Lim
S
,
Khoo
R
,
Peh
KM
, et al
.
bioPROTACs as versatile modulators of intracellular therapeutic targets including proliferating cell nuclear antigen (PCNA)
.
Proc. Natl. Acad. Sci
.
2020
;
117
(
11
):
5791
-
5800
.
137.
Hatakeyama
S
,
Watanabe
M
,
Fujii
Y
,
Nakayama
KI
.
Targeted destruction of c-Myc by an engineered ubiquitin ligase suppresses cell transformation and tumor formation
.
Cancer Res
.
2005
;
65
(
17
):
7874
-
7879
.
138.
Pan
T
,
Zhang
Y
,
Zhou
N
, et al
.
A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth
.
Oncotarget
.
2016
;
7
(
28
):
44299
-
44309
.
139.
Liu
C
,
Shi
Q
,
Huang
X
,
Koo
S
,
Kong
N
,
Tao
W
.
mRNA-based cancer therapeutics
.
Nat Rev Cancer
.
2023
;
23
(
8
):
526
-
543
.
140.
Yang
J
,
Sun
J
,
Zhu
J
, et al
.
Circular mRNA encoded PROTAC (RiboPROTAC) as a new platform for the degradation of intracellular therapeutic targets
.
bioRxiv
.
Preprint posted online 22 April 2022
.
141.
Jin
Y-H
,
Lu
M-C
,
Wang
Y
, et al
.
Azo-PROTAC: novel light-controlled small-molecule tool for protein knockdown
.
J Med Chem
.
2020
;
63
(
9
):
4644
-
4654
.
142.
Pfaff
P
,
Samarasinghe
KTG
,
Crews
CM
,
Carreira
EM
.
Reversible spatiotemporal control of induced protein degradation by bistable PhotoPROTACs
.
ACS Cent Sci
.
2019
;
5
(
10
):
1682
-
1690
.
143.
Xue
G
,
Wang
K
,
Zhou
D
,
Zhong
H
,
Pan
Z
.
Light-induced protein degradation with photocaged PROTACs
.
J Am Chem Soc
.
2019
;
141
(
46
):
18370
-
18374
.
144.
Zhang
Q
,
Kounde
CS
,
Mondal
M
, et al
.
Light-mediated multi-target protein degradation using arylazopyrazole photoswitchable PROTACs (AP-PROTACs)
.
Chem Commun
.
2022
;
58
(
78
):
10933
-
10936
.
145.
Yang
C
,
Yang
Y
,
Li
Y
,
Ni
Q
,
Li
J
.
Radiotherapy-triggered proteolysis targeting chimera prodrug activation in tumors
.
J Am Chem Soc
.
2023
;
145
(
1
):
385
-
391
.
146.
Liu
H
,
Ren
C
,
Sun
R
, et al
.
Reactive oxygen species-responsive pre-PROTAC for tumor-specific protein degradation
.
Chem Commun
.
2022
;
58
(
72
):
10072
-
10075
.
147.
Shi
S
,
Du
Y
,
Zou
Y
, et al
.
Rational design for nitroreductase (NTR)-responsive proteolysis targeting chimeras (PROTACs) selectively targeting tumor tissues
.
J Med Chem
.
2022
;
65
(
6
):
5057
-
5071
.
148.
Xue
Y
,
Bolinger
AA
,
Zhou
J
.
Novel approaches to targeted protein degradation technologies in drug discovery
.
Expert Opin Drug Dis
.
2023
;
18
(
4
):
467
-
483
.
149.
Dong
G
,
Ding
Y
,
He
S
,
Sheng
C
.
Molecular glues for targeted protein degradation: from serendipity to rational discovery
.
J Med Chem
.
2021
;
64
(
15
):
10606
-
10620
.
150.
Słabicki
M
,
Kozicka
Z
,
Petzold
G
, et al
.
The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K
.
Nature
.
2020
;
585
(
7824
):
293
-
297
.
151.
Dikic
I
.
Proteasomal and autophagic degradation systems
.
Annu Rev Biochem
.
2017
;
86
(
1
):
193
-
224
.
152.
Paudel
RR
,
Lu
D
,
Roy Chowdhury
S
,
Monroy
EY
,
Wang
J
.
Targeted protein degradation via lysosomes
.
Biochemistry
.
2023
;
62
(
3
):
564
-
579
.
153.
Ding
Y
,
Xing
D
,
Fei
Y
,
Lu
B
.
Emerging degrader technologies engaging lysosomal pathways
.
Chem Soc Rev
.
2022
;
51
(
21
):
8832
-
8876
.
You do not currently have access to this content.
Sign in via your Institution