Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3

Article abstract of DOI:10.1021/acsmedchemlett.0c00517

Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as drivers of numerous types of cancer with multiple drugs approved or entering late stage clinical trials. A limitation of current inhibitors is vulnerability to gatekeeper resistance mutations. Using a combination of targeted high-throughput screening and structure-based drug design, we have developed a series of aminopyrazole based FGFR inhibitors that covalently target a cysteine residue on the P-loop of the kinase. The inhibitors show excellent activity against the wild-type and gatekeeper mutant versions of the enzymes. Further optimization using SAR analysis and structure-based drug design led to analogues with improved potency and drug metabolism and pharmacokinetics properties.

Full text of DOI:10.1021/acsmedchemlett.0c00517

pubs.acs.org/acsmedchemlett
Letter
Discovery of Aminopyrazole Derivatives as Potent Inhibitors of
Wild-Type and Gatekeeper Mutant FGFR2 and 3
Ryan A. Brawn,* Andrew Cook, Kiyoyuki Omoto, Jiyuan Ke, Craig Karr, Federico Colombo,
Milena Virrankoski, Sudeep Prajapati, Dominic Reynolds, David M. Bolduc, Tuong-Vi Nguyen,
Patricia Gee, Deanna Borrelli, Benjamin Caleb, Shihua Yao, Sean Irwin, Nicholas A. Larsen,
Anand Selvaraj, Xuesong Zhao, and Stephanos Ioannidis
Cite This: https://dx.doi.org/10.1021/acsmedchemlett.0c00517
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ABSTRACT: Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as
drivers of numerous types of cancer with multiple drugs approved or entering late stage clinical
trials. A limitation of current inhibitors is vulnerability to gatekeeper resistance mutations.
Using a combination of targeted high-throughput screening and structure-based drug design,
we have developed a series of aminopyrazole based FGFR inhibitors that covalently target a
cysteine residue on the P-loop of the kinase. The inhibitors show excellent activity against the
wild-type and gatekeeper mutant versions of the enzymes. Further optimization using SAR
analysis and structure-based drug design led to analogues with improved potency and drug
metabolism and pharmacokinetics properties.
KEYWORDS: FGFR, FGFR2, FGFR3, kinase inhibitor, gatekeeper mutant, RTK
berrant signaling of the fibroblast growth factor receptor
A(FGFR) family of receptor tyrosine kinases (RTKs) has
been shown to be a driver in a variety of tumors.1−3 Enzymes
in this family have emerged as promising targets for drug
discovery, with numerous FGFR inhibitors entering the clinic
in the past decade.4−6 The recent approvals of erdafitinib (1)
in FGFR3-aberrant bladder cancer7,8 and pemigatinib (2) in
FGFR2-aberrant cholangiocarcinoma9,10 have clinically vali-
dated FGFR as a quality target for drug development.
Numerous other FGFR and pan-RTK inhibitors are entering
late stage clinical trials targeting tumors with FGFR activating
mutations or fusions, including futibatinib (3)11,12 and
infigratinib (4).13,14
A common issue with RTK inhibition as a therapeutic mode
is the development of resistance mutations in the tumors,
Figure 1. Some approved and clinical FGFR inhibitors.
leading to eventual disease recurrence.15,16 The most common
resistance mechanism to RTK inhibitors is the gatekeeper
mutation, where a bulkier amino acid side chain “blocks”
access to the back pocket of the kinase, a hydrophobic
selectivity pocket that many RTK inhibitors take advantage of
to gain potency and selectivity. Most first and second
generation FGFR inhibitors take advantage of this back
pocket, often using a functionalized dimethoxyphenyl ring
(highlighted in red in Figure 1) to gain FGFR selectivity and
enhance overall potency of the binders. While this has been a
successful strategy, it leaves these inhibitors susceptible to
acquired resistance through gatekeeper mutations, some of
which are starting to arise in clinical samples.17
Many second and third generation RTK inhibitor programs
are centered on overcoming gatekeeper resistance while
attempting to maintain potency and selectivity against the
wild-type version of the kinase.18,19 The aim of our next
Received: September 25, 2020
Accepted: November 25, 2020
https://dx.doi.org/10.1021/acsmedchemlett.0c00517
© XXXX American Chemical Society
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generation FGFR inhibitor program was to identify and
develop a series of inhibitors with activity against both wild-
type and gatekeeper mutant variants of the FGFR2 and FGFR3
kinases. The most clinically relevant gatekeeper mutants are
FGFR2-V564F and FGFR3-V555M. To overcome the
potential loss of potency and kinase selectivity from avoiding
the backpocket of the kinase, we intended to covalently target
the P-loop cysteine that is conserved in all four isoforms of
FGFR but is only present in five other human kinases.20
Our endeavor started with a targeted high-throughput screen
using a deck of ∼10 000 compounds enriched with known
hinge binders. The compounds were screened at a single
concentration of 10 μM in a FRET assay using the FGFR3
V555M gatekeeper mutant protein. IC50 curves were generated
for all “hit” molecules, followed by screening in cellular BaF3
lines engineered for sensitivity toward inhibition of wild-type
and V555M FGFR3. This screening funnel produced a number
of interesting “hit” compounds including compound 1 (Figure
2), which had sub-micromolar potency against both wild-type
were properly aligned to potentially interact with the cysteine
on the flexible P-loop of the kinase. Addition of an acrylamide
to the meta (compound 2, Figure 2) and para (3) positions of
the phenyl ring gave dramatic boosts in potency, with
compound 3 exhibiting single-digit nanomolar activity in
both the wild-type and gatekeeper mutant FGFR3 cell lines.
This compound immediately became the lead molecule for the
program and was pushed forward into hit-to-lead optimization.
Interestingly, the isomer of the pyrimidine was key to potency,
and switching the position of one nitrogen (4) led to a
substantial potency loss. This observation is probably due to
steric repulsion between the C−H proton on the pyrimidine
and the C−H proton on the pyrazole that keeps the molecule
from adopting the ideal orientation to both bind the hinge and
covalently modify the P-loop cysteine.
To further optimize compound 3, we obtained an X-ray
crystal structure in FGFR2 V564F (Figure 4), which showed
Figure 4. X-ray structure of compound 3 in FGFR2 V564F (PDB
code 7KIE).
good density except for the acrylamide/P-loop, confirming that
this part of the molecule is very flexible. Mass spectroscopy
experiments confirmed that 3 covalently modified the protein
(see the Supporting Information for details). Further
optimization of compound 3 started with changes to the
pyrazole hinge binder after analysis of the crystal structure
revealed a small lipophilic pocket where we could gain
additional potency without entering the back pocket and
losing activity against the gatekeeper mutant. Small changes to
the methyl group at the 5-position of the pyrazole could give a
boost in potency (Table 1). The most potent group was the
isopropyl in compound 6, although other small aliphatic
groups and ethers were also tolerated. We also explored some
alternative hinge binders and found that thiazoles and
imidazoles also gave single-digit nanomolar potency against
both wild-type and gatekeeper mutant FGFR3. The polarized
C−H bonds in these heterocycles can act as hydrogen bond
donors that make hinge interactions similar to those observed
in the pyrazole N−H. Synthesis of all of the compounds was
straightforward, using selective couplings (Buchwald, Suzuki,
SNAr) to commercially available 2,4,6-trichloropyrimidine (see
the Supporting Information for synthetic details).
Figure 2. Initial lead compounds.
and mutant FGFR3 in cells. Compound 1 is a known Aurora
kinase A inhibitor with some reported activity against wild-type
FGFR3.21 After computational docking of the hit into a known
FGFR2 X-ray structure (PDB code 4RWKB, Figure 3), we
added acrylamide electrophiles to the phenyl ring so that they
Compound 6 had potency against wild-type FGFR3 similar
to the most potent reported FGFR inhibitors22 while retaining
sub-nanomolar potency against the gatekeeper mutant.
Accordingly, it was further profiled in our testing cascade
including in vitro drug metabolism and pharmacokinetics
(DMPK) assays. Compound 6 showed sub-nanomolar potency
against BaF3 FGFR2 WT and V564F gatekeeper mutant cell
Figure 3. Docking model of compound 1 in FGFR2 V564F.
B
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Table 1. Optimization of the Hinge Binder
Table 2. Profile of Compound 6
assay
result
1.7
1.0
0.1
0.1
9.4
FRFR2 V564F FRET IC50 (nM)
FRFR3 V555 M FRET IC50 (nM)
BaF3 FGFR2 WT GI50 (nM)
BaF3 FGFR2 V564F GI50 (nM)
RT112 GI50 (nM)
BaF3 FGFR1/4 GI50 (nM)
Caco2 A→B (10−6 cm/s)
0.3/6.4
0.1
blood stability hu/mu (t1/2, min)
MLM/HLM CLint (μL/min/mg)
kinetic solubility (μM)
121/114
65/35
43
86.3
3.1
21
103
400
a
mouse CLtotal (mL/min/kg)
a
mouse Vss (L/kg)
mouse %F
b
b
mouse PO Cmax (ng/mL)
a
b
mouse PK PO AUC_obs (ng h/mL)
a
CD-1 male mouse PK dosed IV at 5 mg/kg (formulation: 20% HP-
b
β-CD in DI water). Dosed PO at 10 mg/kg (formulation: 0.1%
Tween and 0.5% CMC in water).
which was low, suggesting that the acrylamide electrophile was
likely susceptible to addition of glutathione or other
nucleophiles present in human and murine whole blood.23
Compound 6 was run in mouse PK to establish a baseline for
the program. As expected from the in vitro DMPK data, the
clearance was high while oral bioavailability was moderate.
This reinforced the need to improve metabolism and
permeability to improve PK.
Follow-up compounds to 6 focused on improving metabolic
stability while maintaining the excellent potency against both
the wild-type and gatekeeper mutant variants of FGFR2 and 3.
Therefore, we explored changes in the linker to the P-loop and
the acrylamide electrophile (Table 3). We envisioned that such
changes might also mitigate the susceptibility of the acrylamide
to whole blood deactivation. For the linker, we were looking to
move away from the olefin/aromatic system, which was
presumed as a potential metabolic liability. For the electro-
phile, we wanted to explore nonaniline based functionalities to
lower the reactivity of the electrophile.
Saturating the olefin (15) led to a substantial loss in
potency, suggesting that a rigid linker was important to
maintain activity. Using a known phenyl bioisostere in 16 also
led to a significant potency drop but also to a significant
improvement in whole blood and microsomal stability,
indicating the culpability of the aniline acrylamide as our
major metabolic liability. A series of nitrogen-containing
heterocycles linked to the core by a phenyl ring were also
profiled (17−19). While the azetidine (17) and pyrrolidine
(18) were more potent, the piperidine (19) showed the most
promising in vitro DMPK profile. Attempts to improve the
potency of 19 by adding small lipophilic (20) or polar (21)
groups to the pyrazole surprisingly gave a minimal boost in
potency. Further attempts to optimize the linker to the P-loop
included a variety of sp3-rich linked and spirocyclic hetero-
a
All cellular assay data reported as an average of a minimum of two
runs.
lines and single digit nanomolar activity against the RT112 cell
line containing an endogenous FGFR3-TACC3 fusion (Table
2). Like most FGFR inhibitors, compound 6 retained activity
against FGFR1, while showing some selectivity against FGFR4.
While the potency was excellent across the board, the overall
profile of this lead needed some improvement. Caco-2
permeability was low, while solubility and stability in mouse
and human liver microsomes were moderate. The bigger
concern was the stability in human and mouse whole blood,
C
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Table 3. Optimization of Linker to the P-Loop
a
Data reported for racemic compound.
cycles (22−24). Many of these compounds had reasonable
potency and improved blood and/or microsomal stability
compared to the original lead, although Caco-2 permeability
from apical-to-basolateral was a persistent issue.
Compound 19 showed the most promising combination of
potency and DMPK profile, so it was further profiled and
carried forward into mouse PK studies (Table 4). This
compound has modest potency across all cell lines profiled and
D
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the Supporting Information for details). Current work is
looking at replacements for the methylpiperazine that can gain
additional interactions around the solvent pocket and
identification of any problematic off-target activity and further
optimization of the linker to the P-loop to help find the
optimal balance between potency and PK.
Table 4. Profile of Compound 19
In conclusion, we have developed a series of novel 3-
aminopyrazoles that show appreciable activity against both
wild-type and gatekeeper mutant FGFR2 and 3 by utilizing
covalent modification of a P-loop cysteine residue. Modifica-
tions of the linker that positions the electrophile in proximity
to the P-loop has resulted in analogues with improved profiles
that culminated in the identification of 19. Current leading
analogues seem to display similar in vitro wild-type activity to
the current leading clinical FGFR2/3 inhibitors. Further work
will focus on finding the appropriate balance between potency
and DMPK properties in this series.
assay
result
49
111
FRFR2 V564F FRET IC50 (nM)
FRFR3 V555 M FRET IC50 (nM)
BaF3 FGFR2 WT GI50 (nM)
RT112 GI50 (nM)
BaF3 FGFR1/4 GI50 (nM)
BaF3 parental GI50 (nM)
11.2
52.9
25.1/438
2327
115
27/4.4
53.6
2.0
ASSOCIATED CONTENT
* Supporting Information
kinetic solubility (μM)
■
hepatocyte stability CLintmu/hu (μL/min/106 cells)
mouse CLtotal (mL/min/kg)
sı
a
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00517.
a
mouse Vss (L/kg)
mouse %F
b
68
734
2100
Synthetic procedures, compound characterization, assay
methods and conditions, and crystal structure data
(PDF)
b
mouse PO Cmax (ng/mL)
a
b
mouse PK PO AUC_obs (ng h/mL)
a
CD-1 Male Mouse PK dosed IV at 5 mg/kg (formulation: 20% HP-
β-CD in DI water). Dosed PO at 10 mg/kg (formulation: 0.1%
Tween and 0.5% CMC in water).
b
AUTHOR INFORMATION
Corresponding Author
■
some selectivity against FGFR4. A BaF3 parental cell line was
used to assess general cytotoxicity, and while there was some
activity, there was a significant window compared to the on-
target lines. Dosing (19) via the IV route at a 5 mg/kg dose
level showed moderate clearance, while an oral dose of 10 mg/
kg displayed good bioavailability and oral exposure. The profile
of (19) indicated that this series is amenable to optimization
by demonstrating a reasonable in vitro/in vivo DMPK
correlation. An X-ray crystal structure of 19 (Figure 5) was
Ryan A. Brawn − H3 Biomedicine, Cambridge, Massachusetts
02139, United States; orcid.org/0000-0003-0714-8182;
Email: ryan_brawn@h3biomedicine.com
Authors
Andrew Cook − H3 Biomedicine, Cambridge, Massachusetts
02139, United States
Kiyoyuki Omoto − H3 Biomedicine, Cambridge,
Massachusetts 02139, United States
Jiyuan Ke − H3 Biomedicine, Cambridge, Massachusetts
02139, United States
Craig Karr − H3 Biomedicine, Cambridge, Massachusetts
02139, United States
Federico Colombo − H3 Biomedicine, Cambridge,
Massachusetts 02139, United States
Milena Virrankoski − H3 Biomedicine, Cambridge,
Massachusetts 02139, United States
Sudeep Prajapati − H3 Biomedicine, Cambridge,
Massachusetts 02139, United States
Dominic Reynolds − H3 Biomedicine, Cambridge,
Massachusetts 02139, United States
David M. Bolduc − H3 Biomedicine, Cambridge,
Massachusetts 02139, United States; orcid.org/0000-
0003-2003-8631
Figure 5. X-ray structure of compound 19 in FGFR2 V564F (PDB
code 7KIA).
Tuong-Vi Nguyen − H3 Biomedicine, Cambridge,
Massachusetts 02139, United States
Patricia Gee − H3 Biomedicine, Cambridge, Massachusetts
02139, United States
Deanna Borrelli − H3 Biomedicine, Cambridge,
Massachusetts 02139, United States
Benjamin Caleb − H3 Biomedicine, Cambridge,
Massachusetts 02139, United States
Shihua Yao − H3 Biomedicine, Cambridge, Massachusetts
02139, United States
obtained, and it will be used for further modifications as we
continue to search for the optimal balance between potency
and PK in this series. Mass spectrometry analysis confirmed
that the compound is covalently modifying the P-loop cysteine
in FGFR.
A handful of the lead compounds were put into a DiscoverX
mini-kinase panel to check binding to other kinases against
which FGFR inhibitors have reported off-target activity (see
E
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Letter
JNJ-42756493 (erdafitinib), a functionally selective small-molecule
FGFR family inhibitor. Mol. Cancer Ther. 2017, 16, 1010−1020.
(8) Announcement from the Janssen website, April 12, 2019.
https://www.janssen.com/balversa-erdafitinib-receives-us-fda-
approval-treatment-patients-locally-advanced-or-metastatic.
(9) Liu, P. C. C.; Koblish, H.; Wu, L.; Bowman, K.; Diamond, S.;
DiMatteo, D.; et al. INCB054828 (pemigatinib), a potent and
selective inhibitor of fibroblast growth factor receptors 1, 2, and 3,
displays activity against genetically defined tumor models. PLoS One
2020, 15, No. e0231877.
(10) Press release from the Incyte website, April 17, 2020. https://
investor.incyte.com/press-releases/press-releases/2020/FDA-
Approves-Incytes-Pemazyre-pemigatinib-as-First-Targeted-
Treatment-for-Adults-with-Previously-Treated-Unresectable-Locally-
Advanced-or-Metastatic-Cholangiocarcinoma/default.aspx.
(11) Ochiiwa, H.; Fujita, H.; Itoh, K.; Sootome, H.; Hashimoto, A.;
Fujioka, Y.; Nakatsuru, Y.; Oda, N.; Yonekura, K.; Hirai, H.; Utsugi,
T. TAS-120, a highly potent and selective irreversible FGFR inhibitor,
is effective in tumors harboring various FGFR gene abnormalities.
Mol. Cancer Ther. 2013, 12, A270.
Sean Irwin − H3 Biomedicine, Cambridge, Massachusetts
02139, United States
Nicholas A. Larsen − H3 Biomedicine, Cambridge,
Massachusetts 02139, United States
Anand Selvaraj − H3 Biomedicine, Cambridge, Massachusetts
02139, United States
Xuesong Zhao − H3 Biomedicine, Cambridge, Massachusetts
02139, United States
Stephanos Ioannidis − H3 Biomedicine, Cambridge,
Massachusetts 02139, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.0c00517
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
(12) Clinical trial information, October 2020. https://clinicaltrials.
gov/ct2/show/NCT02052778?term=TAS-120.
The authors declare no competing financial interest.
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the compound when the acrylamide is saturated.
ACKNOWLEDGMENTS
■
The authors would like to thank the H3 leadership team for
supporting this publication and our co-workers for helpful
discussions and advice.
ABBREVIATIONS
■
FGFR, fibroblast growth factor receptor; RTK, receptor
tyrosine kinase; WT, wild-type; PDB, Protien Data Bank;
FRET, fluorescence resonance energy transfer; nM, nano-
molar; HLM, human liver microsomes; MLM, mouse liver
microsomes; mu/hu, mouse/human; t1/2, half-life; Clint,
intrinsic clearance; μL, microliter; μM, micromolar; Cltotal,
total clearance; Vss, volume of distribution; %F, percentage
bioavailability; PO, oral dosing; Cmax, maximum concen-
tration in blood; ng, nanograms; AUC_obs, observed area
under the curve; HP-β-CD, beta-cyclodextrin; CMC, carbox-
ymethylcellulose sodium
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