Discovery of a Potent Degrader for Fibroblast Growth Factor Receptor 1/2

Article abstract of DOI:10.1002/anie.202101328

Aberrant activation of FGFR signaling occurs in many cancers, and ATP-competitive FGFR inhibitors have received regulatory approval. Despite demonstrating clinical efficacy, these inhibitors exhibit dose-limiting toxicity, potentially due to a lack of selectivity amongst the FGFR family and are poorly tolerated. Here, we report the discovery and characterization of DGY-09-192, a bivalent degrader that couples the pan-FGFR inhibitor BGJ398 to a CRL2^VHL E3 ligase recruiting ligand, which preferentially induces FGFR1&2 degradation while largely sparing FGFR3&4. DGY-09-192 exhibited two-digit nanomolar DC₅₀s for both wildtype FGFR2 and several FGFR2-fusions, resulting in degradation-dependent antiproliferative activity in representative gastric cancer and cholangiocarcinoma cells. Importantly, DGY-09-192 induced degradation of a clinically relevant FGFR2 fusion protein in a xenograft model. Taken together, we demonstrate that DGY-09-192 has potential as a prototype FGFR degrader.

Full text of DOI:10.1002/anie.202101328

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Discovery of a Potent Degrader for Fibroblast Growth Factor
Receptor 1/2
Authors: Guangyan Du, Jie Jiang, Qibiao Wu, Nathaniel J Henning,
Katherine A Donovan, Hong Yue, Jianwei Che, Wenchao
Lu, Eric S Fischer, Nabeel Bardeesy, Tinghu Zhang, and
Nathanael Schiander Gray
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202101328
Link to VoR: https://doi.org/10.1002/anie.202101328

10.1002/anie.202101328
Angewandte Chemie International Edition
RESEARCH ARTICLE
Discovery of a Potent Degrader for Fibroblast Growth Factor
Receptor 1/2
Guangyan Du+[a], Jie Jiang+[a], Qibiao Wu+[b], Nathaniel J. Henning[a], Katherine A. Donovan[a], Hong
Yue[a], Jianwei Che[a], Wenchao Lu[a], Eric S. Fischer[a], Nabeel Bardeesy*[b], Tinghu Zhang*[c], and
Nathanael S. Gray*[c]
Dedication ((optional))
[a]
[b]
Dr. G. Du, Dr. J. Jiang, N. J. Henning, Dr. K. A. Donovan, Dr. H. Yue, Dr. J. Che, Dr. W. Lu, and Dr. E. S. Fischer.
Department of Cancer Biology, Dana Farber Cancer Institute, 360 Longwood Ave, Boston, Massachusetts, 02215, USA;
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Dr. Q. Wu, and Dr. N. Bardeesy.
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
E-mail: bardeesy.nabeel@mgh.harvard.edu
[c]
[+]
Dr. T. Zhang and Dr. N. S. Gray
Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA
93405, USA.
E-mail: tzhang8@stanford.edu, nsgray01@stanford.edu
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document
Abstract: Aberrant activation of FGFR signaling occurs in many
cancers, and ATP-competitive FGFR inhibitors have received
regulatory approval. Despite demonstrating clinical efficacy, these
inhibitors exhibit dose-limiting toxicity, potentially due to a lack of
selectivity amongst the FGFR family and are poorly tolerated.
Here, we report the discovery and characterization of DGY-09-
192, a bivalent degrader that couples the pan-FGFR inhibitor
BGJ398 to a CRL2VHL E3 ligase recruiting ligand, which
preferentially induces FGFR1&2 degradation while largely
sparing FGFR3&4. DGY-09-192 exhibited two-digit nanomolar
DC50s for both wildtype FGFR2 and several FGFR2-fusions,
resulting in degradation-dependent antiproliferative activity in
representative gastric cancer and cholangiocarcinoma cells.
Importantly, DGY-09-192 induced degradation of a clinically
relevant FGFR2 fusion protein in a xenograft model. Taken
together, we demonstrate that DGY-09-192 has potential as a
prototype FGFR degrader.
FGFR1 signaling has been identified as a mechanism of adaptive
resistance to RTK/RAS/MEK pathway inhibition.
The oncogenic role of aberrant FGFR signaling has prompted
extensive efforts to develop therapeutic agents targeting this
pathway.[4] First-generation FGFR inhibitors, such as dovitinib,[5]
nintedanib (BIBF1120),[6] and ponatinib (AP23534),[7] are multi-
targeted agents that potently inhibit VEGFR and PDGFR.
Although ponatinib[7b] and nintedanib[8] are approved for the
treatment of myeloid leukemia and non-small-cell lung cancer,
respectively, the toxicity profile of these agents limits their
therapeutic doses.
To improve selectivity, a strategy of covalently targeting the
conserved cysteine on the activation loop of FGFR paralogs has
been achieved by FIIN1-3,[9] PRN1371,[10] BLU554,[11] and TAS-
120.[12] Separately, second generation reversible FGFR inhibitors
such as AZD4547,[13] BGJ398,[14] JNJ-42756493[15] and
INCB054828[16] have improved selectivity for the FGFR family and
have demonstrated efficacy against FGFR-dependent cancers in
clinical trials, leading to the recent approval of JNJ-42756493 and
INCB054828 for the treatment of advanced urothelial and biliary
tract cancers, respectively (Figure 1). Nevertheless, despite
significant progress in the development of potent and selective
FGFR inhibitors over the last decade, the long-term efficacy of
these agents in cancer treatment has been hampered by the rapid
onset of acquired resistance, occurring commonly through the
mutation of the gatekeeper residue. For example, while the
covalent inhibitor TAS-120 is effective against some FGFR
mutants, it cannot overcome the gatekeeper mutation.[17]
Moreover, cancer cells may develop resistance to covalent
inhibitors like TAS-120 by mutating the residue targeted by the
inhibitor, a resistance mechanism previously demonstrated for
BTK[18] and EGFR[19] covalent inhibitors.
Introduction
The human genome encodes four FGFRs (FGFR1-4), with
FGFR4 being the most divergent.[1][2] This family of receptor
tyrosine kinases and their ligands exhibit highly specific temporal
and spatial expression patterns and regulate diverse
physiological processes including embryogenesis, angiogenesis,
metabolism, fibrogenesis, proliferation, and differentiation.
Dysregulation of FGFR signaling is an oncogenic driver in
many cancers, including breast, biliary tract, gastro-esophageal,
and hepatocellular carcinomas[3], and can occur through receptor
or ligand overexpression, gene amplification, activating mutations,
or chromosomal fusions. Moreover, feedback activation of
1
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10.1002/anie.202101328
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RESEARCH ARTICLE
Table 1. Biochemical IC50s of BGJ398-glutarimide based degraders.
Compound
Linker
E3
binder
FGFR2 IC50
(nM)[a]
DGY-09-037
DGY-09-073
DGY-09-038
DGY-09-036
DGY-09-041
A
B
A
A
A
51
33
63
54
23
[a] All the IC50s are measured by Z’-LYTE kinase assay by Invitrogen.
Table 2. Biochemical IC50s of FIIN2- IMiDs based degraders.
Figure 1. Structures of selective FGFR inhibitors.
Moreover, second generation FGFR inhibitors are pan-FGFR
20]
inhibitors with class-specific on-target toxicities.[15a,
Many
patients require dose reduction, and thus drug exposure within
tumors may be sub-optimal. Thus, inhibitors with selectivity within
the FGFR family could be therapeutically beneficial. However,
given the high structural similarity in the ATP-binding pocket
between FGFR1-3, developing selective inhibitors is challenging
and none have been reported to date. Currently, the only small
molecule with selectivity within the FGFR family is BLU554, which
targets a unique cysteine (Cys 554) located in the hinge region of
FGFR4.[15]
Compound
Linker
E3 binder
FGFR2 IC50
(nM)[a]
DGY-09-068
DGY-09-074
DGY-09-077
A
B
A
93
42
72
[a] All the IC50s are measured by Z’-LYTE kinase assay by Invitrogen.
We then synthesized several glutarimide-based CRBN-targeting
compounds with various linkers attached via the piperazine
(Table 1&2). The prepared molecules remained potent
biochemical inhibitors of FGFR2 as shown in Table 1&2. Next, we
evaluated whether these compounds induced degradation of the
TEL-FGFR2 fusion protein (which includes the FGFR2 kinase
domain) in Ba/F3 cells. As shown in Figure 2A, 24h treatment
with 1 M of each degrader resulted in reduction of TEL-FGFR2
fusion protein levels in Ba/F3 cells. Encouraged by this result, we
then tested these compounds in the KATO III gastric cancer cell
line harboring amplification of full length FGFR2. Surprisingly,
immunoblot analysis revealed no decrease of FGFR2 levels up to
24h treatment (Figure 2B). While the reasons for the differential
degradation observed in the Ba/F3 versus the KATO III cells
remains unclear, potential contributing factors include differences
in protein expression, cellular localization of TEL-FGFR2
(cytoplasmic) compared to FGFR2 (membrane bound), CRBN
availability, and/or ability to form a ternary complex with FGFR2.
To examine whether the nature of the E3 ligase affects the
potency of FGFR2 degraders, we synthesized several bivalent
compounds in which BGJ398 was linked with a VHL recruiting
ligand connected through a variety of exit vectors (Table 3).
Overall, all VHL-based degrader molecules displayed a similar
biochemical inhibition of FGFR2. However, DGY-09-192 showed
Recently, degradation strategies that utilize heterobifunctional
molecules to recruit an E3 ubiquitin ligase complex to a target
protein for ubiquitination and subsequent proteasome-mediated
degradation have been employed to increase target selectivity
when compared to their parental inhibitors[21][22]. For example, a
degrader that was constructed with a promiscuous kinase
inhibitor TAE684 and CRBN ligand caused selective degradation
of only a subset of the TAE684 binding kinase targets.[23]
Furthermore, we have recently developed degraders that can
differentiate among close paralogs within the same family, such
as CDK4 versus CDK6[24] or CDK9 versus other CDKs[25]. Here,
we describe the development, characterization and validation of
DGY-09-192 as a dual degrader of FGFR1 and 2, with minimal
activity towards FGFR3 and 4.
Results and Discussion
To design FGFR degraders, we first examined two high-
resolution crystal structures of FGFR bound to ATP-competitive
inhibitors BGJ398 and FIIN1-3 and identified the solvent-exposed
piperazine as appropriate sites for linker installation.
2
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10.1002/anie.202101328
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RESEARCH ARTICLE
Table 3. Biochemical IC50s of FGFR2 for BGJ398-VHL based degraders.
Compound
Linker
E3 binder
FGFR2 IC50
(nM)[a]
DGY-09-192
NJH-05-166
NJH-05-132
NJH-05-123
NJH-05-043
C
C
C
C
C
34
30
10
16
30
NJH-05-044
C
D
E
F
33
59
43
28
DGY-11-123
DGY-11-122
DGY-09-192-Neg
Figure 2. Screening of IMiDs based degraders. Immunoblot analysis of FGFR2
in A) TEL-FGFR2 Ba/F3 cells and B) Kato III cells treated with the indicated
BGJ398-IMiDs or FIIN2-IMiDs based compounds for 24h.
the most potent degradation of full length FGFR2 protein in KATO
III cells after 24h treatment at 1 µM (Figure 3B). A dose titration
revealed a DC50 of 70 nM (Dmax=74%) after 6h treatment, while
the hook effect was not observed until concentrations above 5 µM
(Figure 3C, S4). A time course displayed signification FGFR2
degradation within 4h, which was sustained up to 16h (Figure 3D).
To investigate whether DGY-09-192 could target different FGFR-
fusion proteins, which might present distinct steric constraints that
affect tertiary complex formation,[27] we tested the compound in
CCLP-1-FP cells with ectopic expression of the FGFR2-PHGDH
fusion and ICC13-7 cells that express the FGFR2-OPTN fusion
endogenously. These fusions contain nearly the full coding
sequence of FGFR2, including the extracellular, transmembrane,
and kinase domains, fused in-frame to partners encoding
dimerization domains. As shown in Figure 3E&F, 100 nM and 1
µM of DGY-09-192 resulted in the dose-dependent degradation
of FGFR fusion proteins in both CCLP-1-FP and ICC13-7 cells.
[a] All the IC50s are measured by Z’-LYTE kinase assay by Invitrogen.
We next inspected the degradation selectivity of DGY-09-192.
We observed that DGY-09-192 is an equally potent inhibitor for all
FGFR isoforms (Table S1). However, immunoblot analysis and
quantitative proteomics indicated that DGY-09-192 is a highly
selective degrader of FGFR1 and 2, while sparing FGFR3 and 4.
As shown in Figure 4A, 100 nM of DGY-09-192 effectively
degraded FGFR1 protein in CCLP1 cells (DC50 = 4.35 nM,
Dmax=85%, Figure S4), but had minimal effects on FGFR3 and
FGFR4 protein levels in JHH7 cells (Figure S5&S6). To further
assess the proteome-wide degradation selectivity, we performed
quantitative mass spectrometry-based proteomics following 5h
treatment in Kelly cells which express both FGFR1 and FGFR2.
As shown in Figure 4B, DGY-09-192 exhibited a high selectivity
for FGFR1 and FGFR2 with PDE6D as an off-target (Figure S7).
PDE6D has a large lipophilic binding pocket and has been
previously reported as a degradable target for both IMiDs and
VHL based degraders.[29]
To investigate whether the observed FGFR2 degradation
induced by DGY-09-192 is VHL-dependent, we synthesized the
negative control compound DGY-09-192-Neg, featuring a VHL
ligand previously shown to exhibit a substantial reduction in VHL
binding affinity[28] (Figure S2). As expected, DGY-09-192-Neg
showed similar biochemical inhibition of FGFR kinase activity as
DGY-09-192 (Table 3), but could not degrade FGFR2 (Figure
3G). In addition, pretreatment with either BGJ398 or VHL ligand
rescued FGFR2 degradation induced by DGY-09-192. Similar
rescue was observed with a proteasome inhibitor (bortezomib)
and a NEDD8 activating E1 enzyme inhibitor (MLN4924), which
inhibits the process of ubiquitination and proteasomal degradation
(Figure 3H). Taken together, these data support a VHL-
dependent mechanism for DGY-09-192 induced FGFR2
degradation.
As the proliferation of KATO III cells is highly dependent on
FGFR2 kinase activity, we next investigated the anti-proliferative
effects of DGY-09-192 in KATO III cells. CellTiter-Glo analysis
revealed that DGY-09-192 had an anti-proliferative IC50 of 1 nM
after 72-hour treatment (Figure 5A). In contrast, the negative
control compound DGY-09-192-Neg exhibited a 70-fold loss in
anti-proliferative activity (IC50 = 77 nM), indicating that FGFR2
degradation contributes significantly to the cell growth inhibition
induced by DGY-09-192. In addition, DGY-09-192 also exhibited
anti-proliferative activities against the FGFR1 overexpressing
CCLP1 cells, FGFR2 fusion-positive ICC13-7 cells and
engineered FGFR2 fusion CCLP-FP cells, with IC50s of 17 nM, 40
nM and 8 nM, respectively, versus 232 nM, 689 nM and 70 nM
upon DGY-09-192-Neg treatment. Importantly, control biliary
cancer cell lines lacking FGFR activation (RBE and SNU1079)
3
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10.1002/anie.202101328
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RESEARCH ARTICLE
A
Figure 3. DGY-09-192 induced degradation of FGFR2 or FGFR2-fusion in a VHL dependent manner. A. Structure of DGY-09-192. B. Immunoblot analysis of
FGFR2 in Kato III cells treated with 1 µM of the indicated compounds for 24h. C. Immunoblot analysis of FGFR2 in Kato III cells treated with indicated concentrations
of DGY-09-192 for 6h. D. Immunoblot analysis of FGFR2 in Kato III cells treated with DGY-09-192 at indicated time points. E. Immunoblot analysis of FGFR2-
PHGDH (FP) fusion in CCLP-1 cells and F) FGFR2-OPTN fusion in ICC13-7 cells treated with DGY-09-192 for 24h. G. Immunoblot analysis of FGFR2 in Kato III
cells treated with DGY-09-192 or DGY-09-192-Neg for 4h. H. Immunoblot analysis of FGFR2 in Kato III cells pretreated for 2h with BGJ398, VHL ligand, Bortezomib
or MLN4924, and then treated with DGY-09-192 for 4h. EV is short for empty vector.
Figure 4. Selectivity of DGY-09-192. A. Immunoblot analysis of FGFR1 in CCLP1 cells or FGFR3/4 in JHH7 cells treated with DGY-09-192 for 16h. B. Quantitative
proteomics showing relative abundance of proteins in Kelly cells treated for 5h with 1 µM.
4
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RESEARCH ARTICLE
Figure 5. Evaluation of DGY-09-192 in FGFR-dependent and independent cell lines. A. RBE and SNU1079 cells (no FGFR abnormalities), Kato III cells (FGFR2
amplication), CCLP1 cells (FGFR1 overexpression) or CCLP-FP (FGFR2-PHGDH fusion) were treated with BGJ398[17], DGY-09-192 and DGY-09-192-Neg for 3d
(ICC13-7 cells for 10d). Cell viability was assessed with CellTiter-Glo. Data are presented as the mean ± SEM (n = 3).(Data see Table S2, Figure S3) B. Immunoblot
analysis of FGFR2-PHGDH fusion and signaling inhibition in CCLP1-FP cells treated with DGY-09-192, DGY-09-192-Neg and BGJ398 with 50 nM for 4,or 8 hours.
were completely insensitive to DGY-09-192 (IC50>10 uM for both)
(Figure 5A). In addition, downstream FGFR2 signaling, evaluated
by phosphorylation of the scaffolding protein FRS2 or ERK, was
durably suppressed by DGY-09-192, whereas DGY-09-192-Neg
had incomplete and transient effects on FGFR signaling (Figure
5B). AKT phosphorylation was not as strongly affected, consistent
and 2) whether degraders can achieve selectivity for specific
FGFR isoforms. Our initial glutarimide-based degraders achieved
degradation of TEL-FGFR2 expressed in murine Ba/F3 cells but
failed to degrade full length FGFR2 protein in KATO III cells. This
limitation was overcome by switching to recruitment of a VHL E3
ligase, which resulted in the discovery of DGY-09-192, a low
nanomolar degrader for both wild type and fusion mutant FGFR2
proteins. In addition, despite retaining equipotent biochemical
inhibition of all four FGFR isoforms, DGY-09-192 displayed highly
selective degradation of FGFR1 and 2, and degradation of either
full-length FGFR2 or FGFR2 fusion proteins led to profound
degradation-dependent antiproliferative activity in multiple
FGFR2-dependent cells. Additionally, our lead degrader DGY-09
with studies of FGFR kinase inhibitors in this cell line [17]
.
Table 4. Pharmacokinetics property of DGY-09-192.
Parameter
Unit
iv (1 mg/kg)
ip (3 mg/kg)
po (10 mg/kg)
T1/2
Tmax
Cmax
AUClast
CL
h
h
5.45
0.08
1.60
2.94
5.58
1.41
4.25
1.33
1.49
7.33
6.84
5.10
1.67
µM
0.01
µM·h
mL/min/kg
L/kg
0.07
1550.77
Vss
Fpo
0.2
Next, we sought to evaluate target engagement and inhibition
of signaling following in vivo administration of DGY-09-192. We
conducted a pharmacokinetics (PK) study in mice following a
single dose of DGY-09-192 via intravenous (IV, 1 mg/kg),
intraperitoneal (IP, 3 mg/kg) injection or oral administration (10
mg/kg). DGY-09-192 exhibited a fairly long half-life (T1/2 of 5h) with
low clearance via IV and IP administration, but negligible oral
bioavailability (Table 4). We then chose to use a CCLP1-FGFR2-
PHGDH xenograft model to assess in vivo degradation. Once
tumors reached ~200 mm3, mice were administered DGY-09-192
(20 or 40 mg/kg, IP QD) for 6d. Immunoblot analysis of tumor
samples isolated 4h after the last dose revealed reduction in both
FGFR2-PHGDH protein levels and phosphorylation of
downstream markers FRS2 and ERK1/2 in a dose-dependent
manner (Figure 6).
Conclusion
Small molecule-induced protein degradation is an emerging
strategy in drug discovery. In contrast to conventional inhibitors,
in which pharmacology is predicated on receptor occupancy,
bivalent degraders demonstrate event driven pharmacology, and
highly potent degraders that act sub-stoichiometrically relative to
their protein targets have been successfully developed for
numerous targets, including BRD4[30] and BTK.[31]
Figure 6. In vivo pharmacodynamics study of DGY-09-192. A. Immunoblot
analysis of lysates from four independent tumors from each treatment group. B.
Quantification of FGFR1, FGFR2, p-FRS2 and p-ERK. (Significantly different: P
< 0.05; tumor size data shown in Figure S8.)
Mutant FGFRs are validated targets in several cancer types but
current drugs not only lack selectivity amongst the closely related
FGFR1, 2, and 3 but also are unable to distinguish between wild-
type and mutant FGFRs. Thus, in this study we sought to explore:
1) whether FGFR and its fusion variants are degradable targets;
-192 features a short, 2-carbon linker, which may present an
advantage with respect to cellular permeability and bioavailability.
5
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10.1002/anie.202101328
Angewandte Chemie International Edition
RESEARCH ARTICLE
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We demonstrated that DGY-09-192 has an acceptable PK profile
and induced degradation of FGFR2 fusion protein in vivo.
However, as a prototype molecule, DGY-09-192 has some
limitations that will need to be overcome. For example, DGY-09-
192 does not improve upon the FGFR parental inhibitor BGJ398
with respect to antiproliferative activity and is unlikely to overcome
BGJ398-induced point mutation on FGFR proteins that confer
resistance (Table S3). In addition, DGY-09-192 still potently
inhibits all FGFR isoforms, so its antiproliferative activity cannot
be attributed solely to degradation alone. Further optimization will
be necessary to reduce FGFR binding, enhance oral
bioavailability, improve selectivity for a particular FGFR, decrease
off-target binding to PDE6D, and increase potency against drug
resistant mutants. Additionally, we envision that degraders that
exhibit selectivity for oncogenic mutants or fusions relative to wild-
type FGFR to achieve enhanced therapeutic index, could also be
developed with further optimization.
[6]
[7]
Acknowledgements
We thank Milka Kostic, Eric Wang and Inchul You for editing the
manuscript. We thank Zhen-Yu Jim Sun for his assistance on 1H
NMR and 13C NMR data collection. We acknowledge funding from
NIH 5 R01 CA218278-02 (NSG and ESF), Pediatric Low-Grade
Astrocytoma Fund at the Pediatric Brain Tumor Foundation (NSG
and ESF), SPORE NIH P50 CA127003 (NSG and NB), V
Foundation for Cancer Research (NSG, NB and TZ) and CCF
award, supported by
Cholangiocarcinoma Foundation (TZ).
a
Research Grant from the
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Conflict of interest
G.D., N.J.H., T.Z., J.J., and N.S.G. are inventors on FGFR2
degrader patent. E.S.F. is a founder, science advisory board
member, and equity holder in Civetta, Jengu (board member), and
Neomorph, an equity holder in C4, and a consultant to Sanofi,
Novartis, Deerfield, and EcoR1. The Fischer lab receives or has
received research funding from Novartis, Astellas, and Ajax.
N.S.G. is a Scientific Founder, member of the Scientific Advisory
Board (SAB) and equity holder in C4 Therapeutics, Syros, Soltego
(board member), B2S, Allorion, Larkspur (board member), Jengu
and Inception. The Gray lab receives or has received research
funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen,
Voroni, Arbella, Deerfield, and Sanofi. N.B. has received research
funding from Taiho. J.C. is a consultant to Soltego, Jengu, Allorion,
and equity holder for Soltego, Allorion, M3 bioinformatics &
technology Inc. The other authors declare no competing interests.
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Entry for the Table of Contents
Current approved FGFR inhibitors lack selectivity within the FGFR family, which may contribute to their poor tolerability. Here, we
describe DGY-09-192, a selective FGFR1&2 degrader that destabilized wildtype FGFR1&2 and FGFR2 fusion proteins, had potent
anti-proliferative activity in FGFR2-dependent cells, and possessed pharmacokinetics properties suitable for in vivo degradation.
Thus, FGFR degradation may be a promising therapeutic approach.
Institute and/or researcher Twitter usernames: @Dana-Farber, @GuangyanD
8
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