Design, Synthesis, and Evaluation of Highly Potent FAK-Targeting PROTACs

Article abstract of DOI:10.1021/acsmedchemlett.9b00372

Focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase, exerts kinase-dependent enzymatic functions and kinase-independent scaffolding functions, both of which are crucial in cancer development, early embryonic development, and reproduction. H

Full text of DOI:10.1021/acsmedchemlett.9b00372

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Letter
Design, Synthesis, and Evaluation of Highly Potent FAK-Targeting PROTACs
Hongying Gao, Yue Wu, Yonghui Sun, Yiqing Yang, and Yu Rao
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00372 • Publication Date (Web): 22 Oct 2019
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Design, Synthesis, and Evaluation of Highly Potent FAK-Targeting
PROTACs
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Hongying Gao,†,‡,⊥ Yue Wu,†,⊥ Yonghui Sun,† Yiqing Yang,†,‡ and Yu Rao*,†
†MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic
Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, P.R. China
‡Tsinghua University-Peking University Joint Center for Life Sciences, Beijing 100084, PR China
KEYWORDS: FAK, PROTAC, Chemical knockdown, Protein degradation.
ABSTRACT: Focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase, exerts kinase-dependent enzymatic
functions and kinase-independent scaffolding functions, both of which are crucial in cancer development, early embryonic
development and reproduction. However, previous efforts for FAK blocking mainly focus on kinase inhibitors. Proteolysis
Targeting Chimeras (PROTACs) are hetero-bifunctional molecules that allow direct post-translational knockdown of
proteins via ubiquitination of a target protein by E3 ubiquitin ligase and subsequent proteasomal degradation. Here, we
designed and synthesized an FAK PROTAC library with FAK inhibitor (PF562271 or VS6063) and CRBN E3 ligand. A novel
FAK-targeting PROTAC, FC-11, showed a rapid and reversible FAK degradation with a picomolar of DC50 in various cell lines
in vitro, which implying that FAK-PROTACs could be useful as expand tools for studying functions of FAK in biological
system and as potential therapeutic agents.
Focal adhesion kinase (FAK, ~125 kDa), also called
protein tyrosine kinase 2 (PTK2), was first reported in 1992
as a member of the non-receptor protein tyrosine kinases
(PTKs) subfamily1. FAK is widely expressed in a variety of
species, including human, rodent, chicken, frog,
drosophila and xenopus, which has a greater than 90%
homology in amino acid sequence2. FAK contains four
linearly arranged functional domains from its N terminus
(Figure 1a): the FERM (band 4.1, Ezrin, Radixin, Moesin)
domain, the catalytic kinase domain, three proline-rich
regions (PRI, PRII, PRIII) and the focal adhesion targeting
(FAT) domain3, 4. FAK FERM domain contains a nuclear
localization sequence (NLS), which has an important role
in cellular regulation by binding to membrane proteins
(growth factor receptors and chemokine receptors) and
nuclear proteins5-7. FAK kinase domain contains the
activation loop and tyrosine sites, which ultimately
regulate FAK kinase activity8. The PRI-III regions and FAT
domain mainly participate in various protein-protein
interactions, similar to FAK FERM domain9. Thus, FAK
exerts kinase-dependent enzymatic functions and kinase-
independent scaffolding functions, both types of function
are crucial in cancer development, early embryonic
FAK kinase inhibitors. As conventional kinase inhibitors
can only act on the protein kinase domain, and may lead
to drug resistance. Thus, developing a practical strategy to
against both kinase-dependent enzymatic functions and
kinase-independent scaffolding functions of FAK is an
urgent and meaningful need for FAK-related diseases.
Proteolysis targeting chimera (PROTAC) is a novel
chemical knockdown technology for the post-translational
proteins of interest. PROTACs are hetero-bifunctional
small molecules containing two recognition moieties: one
specifically binds an E3 ubiquitin ligase, and the other
specifically binds the target protein. PROTAC molecules
can
development, reproduction and so on10-13
.
Although a few FAK small molecule inhibitors were
developed by major pharmaceutical companies, and some
of them have reached clinical trials for varieties of
malignant cancers14-16, essential non-enzymatic functions
of FAK cannot be investigated or blocked with reported
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Figure 1. Introduction to FAK protein and FAK- different FAK-targeting PROTACs with FAK inhibitor
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5
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7
8
PROTACs. a) FAK protein schematic. FAK-PROTACs can
act on both enzymatic and non-enzymatic functions of
FAK, while FAK inhibitor only act on the enzymatic
function of FAK. Y, Phosphotyrosine; S, Phosphoserine; *,
Autophosphorylation site (Tyr397); PR, Proline-Rich
Regions. b) Schematic depiction of the PROTAC strategy.
(PF562271 or VS6063) and ligand of CRBN E3 ligase, which
could contribute to development of potent tools or
potential therapeutic agents for specifically degrading
FAK.
Results and Discussion. Based on the previous studies
of our laboratory, linker length, mode of binding to the
target protein, and relative spatial orientations of the
target protein and E3 ubiquitin ligase are three major
critical factors for achieving efficient degradation of the
target protein. Optimizing the combination of these three
factors is the key to design of potent and specific PROTACs.
To identify the suitable linker length in our FAK-PROTAC
library, we designed linkers of different lengths by
changing the number units of ethylene glycol (e.g. using
diethylene or triethylene glycol). Both the position of the
linker
drive E3 ubiquitin ligase to the target protein, which results
in ubiquitination of the target protein and consequent
proteasome-mediated degradation (Figure 1b)17, 18. Unlike
classic inhibitors, PROTAC eliminates rather than inhibits
both enzymatic and non-enzymatic protein functions
(Figure 1a). Although two FAK-targeting PROTACs have
been reported in previous studies19, 20, the combination of
different E3 ligase ligands with different inhibitors of FAK
could be valuable for improving the activities, drug-like
properties and exploring structure-activity relationship
(SAR). Herein, we designed and synthesized a series of
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Figure 2. Design of FAK-PROTACs. a) Chemical structures of FAK inhibitors. b) Binding model of FAK inhibitor PF562271
with FAK protein. c) General structure of the designed FAK-PROTACs.
Scheme 1. Synthetic route of FAK-PROTACs.
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O O
S
O O
O O
S
S
X
1
2
3
4
5
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7
8
N
N
N
R2 R3
N Cl
CN
a or b
c
d
h
CN
N
N
N
NH2
N
N
H
9
10
or
R1
X = F R1 = CH
R1
R1
R1
5
6
7
R1 = CH R2 = CCF3 R3 = N
R1 = CH R2 = N R3 = CCF3
R1 = N R2 = CCF3 R3 = N
O
1
2
3
4
R1 = CH
R1 = N
R1 = CH
R1 = N
or X = Cl R1 = N
O O
S
Y
O
O
O
N
N
R2 R3
9
N
i
+
OH
N
H
R5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
e
O
N
N
N
N
O
H
H
N3
R1
O2N
O2N
O
8
11
12
13
14
15
R1 = CH R2 = CCF3 R3 = N Y = CONHCH2C CH
R1 = N R2 = CCF3 R3 = N Y = CONHCH2C
R1 = CH R2 = CCF3 R3 = N Y = NHCOC
R1 = N R2 = CCF3 R3 = N Y = NHCOC
R1 = CH R2 = N R3 = CCF3 Y = NHCOC
R5 = H or Et
CH
CH
CH
CH
N
f
H
H2N
O
N
9
H
N
O
O
NH2
O
S
g
N
R4
N
R2
R3
O
R5
O
O
H2N
H2N
N
N
N
N
10
H
H
R1
16 39
-
(FC-1 to FC-24)
Reaction conditions: a) t-BuOK, DMF, reflux, 2 h for compound 1; b) Cs2CO3, MeCN, 70 oC, 20 h for compound 2; c) Pd/C,
H2, EtOH/DMF, rt, 16 h; d) 2,4-dichloro-5-(trifluoromethyl) pyrimidine, TEA, MeOH, rt, overnight; e) i: SOCl2, reflux, ii:
propargulamine, K2CO3, THF rt, 16 h; f) Fe, NH4Cl, EtOH/H2O, reflux, 4 h; g) propiolic acid, DCC, DMAP, DEE/DMF/CHCl3,
rt, 1 h; h) AcOH, t-amyl alcohol, reflux, 4 h; i) CuSO4, sodium ascorbate, t-BuOH/H2O, 70 oC, 8 h.
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connecting to binders and the rigidity of the linker were
also investigated to modulate the interaction of the target
protein and E3 ligase, and thus directly determine
degradation efficacy.
PROTACs with a combination of different FAK ligands,
diverse linkers and the ligand of CRBN based E3 ligase22
(Figure 2c) following a general chemical synthetic route
(Scheme 1). In brief, the F atom was substituted by N-
methyl methanesulfonamide to generate intermediates 1
or 2. Then the cyano group was reduced to primary amine,
which was used to substitute a chloride atom in 2,4-
dichloro-5-(trifluoromethyl) pyrimidine. The selectivity of
this step was not very good, so that two analogues could be
obtained. The remained chloride atom was substituted by
intermediates 9 or 10 subsequently. The final PROTACs
were produced via click chemistry.
In this study, we chose two FAK inhibitors, VS6063 and
PF56227121, as FAK binders, and one PF562271 analogue as
a negative control for FAK binding (Figure 2a). According
to the co-crystal structure of FAK and PF562271 (PDB:
5TOB, Figure 2b), the lactam ring of PF562271 exposed to
solvent region, and do not play a significant role in protein
binding; therefore, they presented suitable sites to link
with ligands of E3 ligase. Based on the above design
principles, we constructed a series of FAK targeting
Table 1. The structures and protein degradation activities of FAK-PROTACs.
O
O
O
O
N
S
N
R4
N
R2 R3
R5
O
O
N
N
N
N
H
H
R1
CRBN Ligand
FAK Ligand
Linker
DR %
(10
DR %
(1
nM)
Compou
nd
R1
R2
R3
N
R4
Linker
R5
H
nM)
O
16
H
N
N
CCF3
71
37
N
N
N
O
H
(FC-1)
N
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O
O
O
17
H
N
1
2
3
4
5
6
7
8
O
N
CCF3
CCF3
CCF3
CCF3
N
N
N
N
H
H
H
H
60
22
81
32
5
N
N
N
O
O
H
(FC-2)
N
N
18
O
O
N
H
N
C
N
H
N
(FC-3)
N
N
N
19
H
N
55
N
H
N
N
H
H
H
O
O
(FC-4)
N
N
9
O
20
H
N
C
C
10
11
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60
65
40
10
N
H
O
O
(FC-5)
N
N
H
N
21
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
CCF3
CCF3
CCF3
CCF3
CCF3
CCF3
CCF3
CCF3
CCF3
CCF3
CCF3
CCF3
CCF3
N
N
N
N
N
N
N
N
N
N
N
N
N
H
H
H
H
H
H
H
H
H
H
H
H
H
30
90
96
92
92
99
94
82
93
90
90
90
95
N
H
(FC-6)
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
H
N
22
H
N
N
N
32
71
O
O
O
(FC-7)
O
O
O
O
O
O
O
O
O
O
O
O
H
N
23
H
N
O
O
(FC-8)
H
N
24
O
N
C
35
40
90
46
30
67
62
62
62
85
N
H
(FC-9)
H
N
25
H
N
H
H
H
H
H
H
H
H
H
O
O
O
(FC-10)
H
N
26
H
N
C
C
C
C
C
C
C
C
O
(FC-11)
H
N
27
O
O
N
(FC-12)
H
H
N
28
O
O
O
O
O
(FC-13)
H
N
29
H
N
(FC-14)
H
N
30
O
O
(FC-15)
H
N
31
(FC-16)
H
N
32
(FC-17)
H
N
33
O
O
(FC-18)
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N
N
H
34
C
C
C
C
C
C
N
N
N
N
N
N
1
2
3
4
5
6
7
8
N
CCF3
CCF3
N
N
H
H
H
H
H
Et
90
85
0
62
40
0
O
H
H
H
H
H
H
(FC-19)
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
N
H
N
35
N
C
(FC-20)
H
N
36
H
N
CF3
(FC-21)
O
O
O
9
10
11
12
13
14
15
16
17
18
19
20
H
N
37
H
N
C
CF3
N
2
0
O
O
(FC-22)
H
N
38
C
CF3
O
N
0
0
N
(FC-23)
H
H
N
39
H
N
CCF3
N
0
0
O
(FC-24)
O
DR, target protein degradation relative to DMSO. The data were repeated in three independent experiments by Western
blot method.
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The degradation efficiency of FAK-PROTACs was first
evaluated in the human ovarian cancer cell line PA1 at 1 and
10 nM with 8 h treatment. We found that FAK-PROTACs
derived from VS6063 or PF562271 with shorter diethylene
or triethylene glycol linkers exhibited higher degradation
activity FC-1: DR (Protein degradation relative to DMSO)10
nM = 71%, FC-4: DR10 nM = 90%, FC-8: DR10 nM = 96%, FC-11:
linkers formed a special conformation with the highest
degradation in these two binding modes.
When the amino group was replaced with a more rigid
alkynyl group in the ligand for binding E3 ligase,
degradation activity was significantly decreased (FC-15 ~
FC-17 vs FC-11, DR1 nM: 62%, 62%, 62% vs 90%, Table 1 and
Figure S1), whereas substitution with a methylene group
bearing similar flexibility to the amide group maintained
degradation activity (FC-18 vs FC-11, DR1 nM: 85% vs 90%,).
These results suggest that the introduction of rigid linking
groups on the side of the CRBN ligand will restrict the
spatial orientation of CRBN, preventing it from getting
close to FAK. Flexible linking groups, however, allow CRBN
to swing toward FAK at a favorable angle to form a special
conformation, and further result in increased degradation
potency.
DR10
= 99% (Table 1 and Figure S1) These results
nM
indicate that a shorter FAK-PROTAC linker is more
conducive to promoting close proximity between CRBN
and FAK.
In our FAK-PROTAC library, the FAK ligands could
present two different orientations of the amide bond (-
NHCO- and -CONH-) for extending (Table 1). Our results
suggest that PROTACs with a carbonyl group closer to
triazole exhibited higher degradation activity (FC-7 ~ FC-9
better than FC-1 ~ FC-3; FC-10 ~ FC-12 better than FC-4 ~
FC-6, Table 1). Therefore, the -NHCO- extending group
provided a better angle and spatial orientation for the
interaction of FAK and CRBN (Figure S2). At the same
time, we observed that the linker length with the highest
degradation efficacy was different for these two binding
modes: diethylene glycol and triethylene glycol linkers
yielded higher degradation activity for -CONH- and -
NHCO-, respectively, which seems the different proper
Finally, the composition of linkers also influences
degradation activity. A comparison of FC-11 (DR1 nM = 90%),
FC-14 (DR1 nM = 67%), FC-19 (DR1 nM = 62%) and FC-20 (DR1
nM = 40%) illustrated that a linker with oxygen atoms could
lead to more efficient degradation, which may be related
to the special conformation forms, cell permeability and
other possible factors of PROTACs. Taken together, our
results revealed that the balance of linkers and binding
modes between FAK and CRBN is critical in the design of
efficient PROTACs.
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Figure 3. FC-11 induced degradation of FAK via ubiquitin-proteasome system. a) Chemical structure of FC-11. b) FAK
degradation at the indicated dose of FC-11. c) Quantitative analysis of FAK levels after FC-11 treated. The cells were treated
by FC-11 at the indicated doses for 8 h in PA1 cells, and the data was collected from three independent experiments. d)
Confirmation of CRBN-based mechanism in driving degradation of FAK upon FC-11 treatment. PA1 cells were treated for 8
h with FC-11 (+, 1 nM; ++, 10 nM; +++ 100 nM) alone, or pomalidomide (10 µM) or PF562271 (10 µM) alone, or combination
of FC-11 with pomalidomide or with PF562271. e) Confirmation of proteasome-based mechanism in driving degradation of
FAK upon FC-11 treatment. PA1 cells were treated for 8 h with FC-11 (+, 1 nM; ++, 10 nM; +++ 100 nM) alone, MG132 (5 µM)
or carfilzomib (5 µM) alone, or a combination of FC-11 with MG132 or with carfizomib.
Due to the potent degradation efficiency, we chose FC-11
(Figure 3a, 3b and 3c) as the probe to establish chemical
FAK-knockdown models in our remaining investigations.
We confirmed that it induced FAK degradation via CRBN-
mediated and proteasome-dependent mechanisms
(Figure 3d and 3e). PA1 cells were treated with an excess
of the CRBN ligand pomalidomide or the FAK ligand
PF562271 to compete with FC-11 for binding to E3 ligase and
FAK, respectively (Figure 3d). As expected, the excess
pomalidomide or PF562271 successfully reduced FAK
degradation induced by FC-11, which confirmed that the
degradation was mediated by CRBN E3 ubiquitin ligase and
required the binding of FC-11 to FAK and CRBN.
Pomalidomide or PF562271 treatment alone (at the same
concentration) can not result degradation. Furthermore, a
combination of proteasome inhibitor (MG132 or
carfilzomib) and FC-11 treatment completely blocked FC-11
induced FAK degradation (Figure 3e). Overall, these
results demonstrate that the fast and efficient FAK
degradation induced by FC-11 is based on a CRBN-
mediated and proteasome-dependent mechanism.
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Figure 4. Highly potent and broad applicability of FC-11. a) Half-maximal degradation concentrations (DC50) of FC-11 for
FAK in different source of cell lines. b) Cellular FAK recovery levels after wash out FC-11 from PA1 cell culture medium. The
cells were treated for 8 h before washout. c) Efficiently decreased pFAKtyr397 levels at the indicated dose of FC-11 for 8 h in
TM3 cells. FC-11 significantly exceeds PF562271 on the decreasing levels of pFAKtyr397. d) Time course reduction of pFAKtyr397
in TM3 cells by FC-11.
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To further assess the efficiency and broad applicability
of FC-11, 5 different cell lines from different species were
used (Figure 4a and Figure S3). Suprisingly, after 8 h
incubation, the half-maximal degradation concentration
(DC50) of all the tested cell lines (both normal and cancer
cell lines) were all at the scale of picomolar. The DC50
showed as: 310 pM in TM3, 80 pM in PA1, 330 pM in MDA-
MB-436, 370 pM in LNCaP, and 40 pM in Ramos cells. As
with previously reported PROTACs23, excess FC-11
exhibited the hook effect in some cell lines (Figure S3). 8
h of FC-11 treatment in PA1 cells resulted in profound FAK
degradation, which recovered to normal levels at least one-
week post-washout (Figure 4b). More importantly, FC-11
significantly outperformed the FAK inhibitor PF562271 in
severely affect proliferation of the tested cell lines than the
FAK inhibitor PF562271 in 3 days drug incubation (Figure
S4), which question the kinase-independent scaffolding
function of FAK being required for cell proliferation in
vitro in the tested cell lines beyond the effect of inhibition
by its kinase-dependent enzymatic activity.
In summary, we demonstrated that one potent FAK
degrader, FC-11, exhibits rapid and highly efficient
degradation of FAK in various cell lines with a DC50 at
picomolar potencies for 8 h treatment. Furthermore, the
degraded FAK proteins can be fully recoved after wash out
PROTAC molecules, which need only about 1 week in vitro
cell lines. However, like the reported FAK PROTACs, the
cell proliferation activity by FAK PROTAC not significantly
beyond FAK inhibitor in the tested cell lines in vitro.
Therefore, more in vivo work is required to understand and
clarify the biological functions of FAK PROTACs. In
addition, the chemical modifications in PROTACs in
comparison with the parental inhibitors could reduce the
binding affinity with targets and improve the selectivity
under most conditions. In particular, PROTACs employ
the ubiquitin-proteasome system with a few components
and steps, which naturally introduces the essential
matching conditions for target degradation and thus
improves the selectivity17, 19, 20, 24, 25. Therefore, FC-11 may
also be used as a highly specific and potent tool to study
the FAK-related biology, which may not only help us to
understand the FAK biology but could also lead to the
development of new therapeutic agents for the therapy of
FAK-related diseases.
the reduction of autophosphorylation of FAK (pFAKtyr397
)
under the same concentration and treatment conditions
(Figure 4c). PF562271 showed an inhibitory effect on
pFAKtyr397 only at a high dose (3 μM), while FC-11 exhibited
a significant effect below 1 nM. Furthermore, in a time-
course experiment, FC-11 rapidly decreased FAK and
pFAKtyr397 levels, leading to more than 50% protein loss
within 1 h at 100 nM in TM3 cells (Figure 4d). The result
demonstrated that the potent FAK PROTAC (FC-11) not
only has a broad application, but also with a high
degradation activities, which dramatically outperform the
FAK inhibitor PF562271 in the reduction of
autophosphorylation of FAK (pFAKtyr397).
Furthermore, we also detected the effect of FC-11
induced FAK degradation on cell proliferation of the tested
cell lines (Figure S4). Like the reported FAK PROTACs19, 20
,
the efficient knockdown of FAK by FC-11 did not more
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The Supporting Information is available free of charge on the
ACS Publications website.
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The FERM domain: organizing the structure and function of FAK.
Nat Rev Mol Cell Biol 2010, 11, 802-14.
Figure S1. The screening of all FAK-PROTACs. Figure S2. The
model of FAK-PROTACs with FAK protein and cereblon
protein. Figure S3. FAK degradation at the indicated dose of
FC-11 in different cell lines for 8 h incubation. Figure S4. Cell
proliferation activities on the tested cell lines. The details of cell
culture, antibodies, chemical materials, synthesis of all
compounds, and 1H-NMR spectra of FC-11.
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Schaller, M. D. Cellular functions of FAK kinases:
insight into molecular mechanisms and novel functions. J Cell Sci
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Brami-Cherrier, K.; Gervasi, N.; Arsenieva, D.;
Walkiewicz, K.; Boutterin, M. C.; Ortega, A.; Leonard, P. G.;
Seantier, B.; Gasmi, L.; Bouceba, T.; Kadare, G.; Girault, J. A.;
Arold, S. T. FAK dimerization controls its kinase-dependent
functions at focal adhesions. EMBO J 2014, 33, 356-70.
AUTHOR INFORMATION
10.
Kessler, B. E.; Sharma, V.; Zhou, Q.; Jing, X.; Pike, L. A.;
Corresponding Author
*E-mail: yrao@tsinghua.edu.cn. Phone: +86-010 62782025.
Kerege, A. A.; Sams, S. B.; Schweppe, R. E. FAK Expression, Not
Kinase Activity, Is a Key Mediator of Thyroid Tumorigenesis and
Protumorigenic Processes. Mol Cancer Res 2016, 14, 869-82.
ORCID
11.
Beraud, C.; Dormoy, V.; Danilin, S.; Lindner, V.; Bethry,
A.; Hochane, M.; Coquard, C.; Barthelmebs, M.; Jacqmin, D.; Lang,
H.; Massfelder, T. Targeting FAK scaffold functions inhibits
human renal cell carcinoma growth. Int J Cancer 2015, 137, 1549-
59.
Hongying Gao: 0000-0001-5078-1317
Yu Rao: 0000-0002-4356-8531
Author Contributions
12.
Gogate, P. N.; Kurenova, E. V.; Ethirajan, M.; Liao, J.;
Yemma, M.; Sen, A.; Pandey, R. K.; Cance, W. G. Targeting the C-
terminal focal adhesion kinase scaffold in pancreatic cancer.
Cancer Lett 2014, 353, 281-9.
⊥These authors contributed equally.
Notes
The authors declare no competing interests.
13.
Gungor-Ordueri, N. E.; Mruk, D. D.; Wan, H. T.; Wong,
E. W.; Celik-Ozenci, C.; Lie, P. P.; Cheng, C. Y. New insights into
FAK function and regulation during spermatogenesis. Histol
Histopathol 2014, 29, 977-89.
ACKNOWLEDGMENT
We thank Dr. Wei Wu, Dr. Xiuyun Sun, and Zimo Yang from
Tsinghua University for their kind help. This work was
supported by the National Natural Science Foundation of
China (#81573277, 81622042, 81773567), National Major
Scientific and Technological Special Project for “Significant
14.
Roberts, W. G.; Ung, E.; Whalen, P.; Cooper, B.; Hulford,
C.; Autry, C.; Richter, D.; Emerson, E.; Lin, J.; Kath, J.; Coleman,
K.; Yao, L.; Martinez-Alsina, L.; Lorenzen, M.; Berliner, M.; Luzzio,
M.; Patel, N.; Schmitt, E.; LaGreca, S.; Jani, J.; Wessel, M.; Marr, E.;
Griffor, M.; Vajdos, F. Antitumor activity and pharmacology of a
selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res
2008, 68, 1935-44.
New
Drugs
Development”
(#SQ2017ZX095003,
2018ZX09711001), and the Tsinghua-Peking University Life
Science Center postdoctoral fellowship.
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Infante, J. R.; Camidge, D. R.; Mileshkin, L. R.; Chen, E.
X.; Hicks, R. J.; Rischin, D.; Fingert, H.; Pierce, K. J.; Xu, H.;
Roberts, W. G.; Shreeve, S. M.; Burris, H. A.; Siu, L. L. Safety,
pharmacokinetic, and pharmacodynamic phase I dose-escalation
trial of PF-00562271, an inhibitor of focal adhesion kinase, in
advanced solid tumors. J Clin Oncol 2012, 30, 1527-33.
ABBREVIATIONS
FAK, Focal adhesion kinase; PTK2, protein tyrosine kinase 2;
PTKs, protein tyrosine kinases; PR, proline-rich regions;
FAT, focal adhesion targeting; NLS, nuclear localization
sequence; PROTACs, Proteolysis Targeting Chimeras.
16.
Lee, B. Y.; Timpson, P.; Horvath, L. G.; Daly, R. J. FAK
signaling in human cancer as a target for therapeutics. Pharmacol
Ther 2015, 146, 132-49.
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Design, Synthesis, and Evaluation of Highly Potent FAK-Targeting
PROTACs
Hongying Gao,†,‡,⊥ Yue Wu,†,⊥ Yonghui Sun,† YiqingYang,†,‡ and Yu Rao*,†
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