Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies

Article abstract of DOI:10.1021/acsmedchemlett.0c00255

Small molecule potent IRAK4 inhibitors from a novel bicyclic heterocycle class were designed and synthesized based on hits identified from Aurigene's compound library. The advanced lead compound, CA-4948, demonstrated good cellular activity in ABC DLBCL and AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed in whole blood assays. CA-4948 demonstrated moderate to high selectivity in a panel of 329 kinases as well as exhibited desirable ADME and PK profiles including good oral bioavailability in mice, rat, and dog and showed >90% tumor growth inhibition in relevant tumor models with excellent correlation with in vivo PD modulation. CA-4948 was well tolerated in toxicity studies in both mouse and dog at efficacious exposure. The overall profile of CA-4948 prompted us to select it as a clinical candidate for evaluation in patients with relapsed or refractory hematologic malignancies including non-Hodgkin lymphoma and acute myeloid leukemia.

Full text of DOI:10.1021/acsmedchemlett.0c00255

pubs.acs.org/acsmedchemlett
Letter
Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for
Treatment of Hematologic Malignancies
Venkateshwar Rao Gummadi, Anima Boruah, Bharathi Raja Ainan, Brahma Reddy Vare, Srinivas Manda,
Hari Prakash Gondle, Shiva Nagendra Kumar, Subhendu Mukherjee, Suraj T. Gore,
Narasimha Rao Krishnamurthy, Sivapriya Marappan, Shilpa S. Nayak, Kavitha Nellore,
Wesley Roy Balasubramanian, Archana Bhumireddy, Sanjeev Giri, Sreevalsam Gopinath,
Dodheri S. Samiulla, Girish Daginakatte, Aravind Basavaraju, Shekar Chelur, Rajesh Eswarappa,
Charamanna Belliappa, Hosahalli S. Subramanya, Robert N. Booher, Murali Ramachandra,
and Susanta Samajdar*
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ABSTRACT: Small molecule potent IRAK4 inhibitors from a
novel bicyclic heterocycle class were designed and synthesized
based on hits identified from Aurigene’s compound library. The
advanced lead compound, CA-4948, demonstrated good cellular
activity in ABC DLBCL and AML cell lines. Inhibition of TLR
signaling leading to decreased IL-6 levels was also observed in
whole blood assays. CA-4948 demonstrated moderate to high
selectivity in a panel of 329 kinases as well as exhibited desirable
ADME and PK profiles including good oral bioavailability in mice,
rat, and dog and showed >90% tumor growth inhibition in relevant
tumor models with excellent correlation with in vivo PD modulation. CA-4948 was well tolerated in toxicity studies in both mouse
and dog at efficacious exposure. The overall profile of CA-4948 prompted us to select it as a clinical candidate for evaluation in
patients with relapsed or refractory hematologic malignancies including non-Hodgkin lymphoma and acute myeloid leukemia.
KEYWORDS: IRAK4, bicyclic heterocycles, SAR, CA-4948, AML, DLBCL
nterleukin-1 receptor associated kinases (IRAKs) are serine/
receptor complex, which then complexes with IRAK4 and
activates IRAK1. TRAF6 is then activated by IRAK1 leading to
NFkB activation.2 Dysregulated activation of the IRAK pathway
in cancer cells further contributes to disease progression through
inflammation of the tumor microenvironment. Waldenstrom’s
Macroglobulinemia (WM) and a subset of activated B cell such
as diffuse large B cell lymphomas (ABC DLBCLs) are
characterized by oncogenic mutations in MYD88 that result in
constitutive activation of the NFkB pathway.3,4 TLRs and their
associated signal transducers are frequently overexpressed and/
or constitutively activated in myelodysplastic syndromes
(MDS). IRAK1 overexpression and activation are also observed
in acute myeloid leukemia (AML).5 Finally, the overexpression
of the oncogenic long form of IRAK4 (IRAK4-L) has been
Ithreonine protein kinases belonging to the tyrosine-like
Figure 1. Clinical stage IRAK4 inhibitors with published chemical
structures.
Received: May 13, 2020
Accepted: October 6, 2020
kinase (TLK) family. Among the members of the IRAK family,
only IRAK1 and IRAK4 exhibit kinase activity.1,2 IRAKs are
downstream effectors of Toll-like receptor (TLR) and
interleukin-1 receptor (IL-1R) pathways and play an important
role in innate immune signaling. TLR stimulation leads to
recruitment of MYD88, an adaptor molecule, to the activated
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Figure 2. Comparison of crystallographic binding modes in the IRAK4 kinase domain showing different active-site interactions in dotted lines: (a) 1
(magenta, RCSB PDB ID: 7C2W) and AMP-PNP (yellow, PDB ID: 2OID). Blue highlighted regions signify possible regions for modification of 1. (b)
1 (magenta, RCSB PDB ID: 7C2W) and CA-4948 (cyan, RCSB PDB ID: 7C2V). (c) Key interaction of CA-4948 in the IRAK4 kinase domain (cyan,
RCSB PDB ID: 7C2V).
Table 1. Optimization of Benzoxazole Amide Hit and Evolution of Aza-benzoxazole Series
a
b
c
d
Calculated using MarvinView6.1.7. Inhibition of LTA induced TNFα release in THP-1 cells. Not determined. IC50’s not determined since the
e
maximum IRAK4 inhibitions observed were less than 90%. Shown as IC50 standard deviation (N = 2).
found in over half of cases of AML and MDS and portends worse
prognosis.6,7 Thus, IRAKs are attractive therapeutic targets for
the treatment of MDS, AML, and other tumors with altered
innate immune signaling.
structurally diverse inhibitors that can be potentially utilized for
treatment of different disease conditions such as chronic
inflammatory diseases, myeloproliferative disorders, and
cancer.10−15 Among these, Pfizer’s PF-0665083313 (Figure 1)
was the first inhibitor to enter the clinic16 and is currently under
investigation in Phase 2 trials for the treatment of rheumatoid
Since the validation of IRAK4 as a drug target,8,9 there have
been a number of public disclosures on potent, selective, and
B
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cellular IC50 < 100 nM (Table 1) but demonstrated poor
aqueous solubility, pH 7.4 (<2 μM) and Caco-2 permeability
(0.4 × 10−6 cm/s).
Table 2. Optimization of Compound 8 in the Gate-Keeper-
Lys213-Asp329 Pocket
Compound 3 having marginally reduced lipophilicity
(cLogDpH7.4 < 3) (Table 1) showed improvement in aqueous
solubility, pH 7.4 (2.4 μM), and Caco-2 permeability (21.4 ×
10−6 cm/s) relative to 5. This observation led us to explore the
introduction of polarity in different parts of the molecule. We
chose the core region first to start this exploration. Careful
analysis of the binding mode of 1 in IRAK4 (Figure 2a) revealed
that introduction of a polar atom in position 4 of the
benzoxazole core is unlikely to affect the binding affinity
because this region appeared to be far from any protein residues
whereas the 7 position may not be amenable to such changes
since it is closer to the hinge and may result in an unfavorable
steric interference with the Met265 backbone carbonyl. We
synthesized compounds 6 and 7 based on this hypothesis, and
the results showed that introduction of the N atom at position 4
is most likely tolerated but not at position 7, since 6 showed
significantly higher IRAK4 inhibition than 7 at 10 μM (Table 1).
This modification also led to significant reduction of lip-
ophilicity of the molecule (cLogDpH7.4 1.8) and consequent
improvement in aqueous solubility, pH 7.4 (9.7 μM). We then
considered 4-aza benzoxazole to be our core of choice, and
compounds 8 and 9 (aza-analogs of compounds 5 and 4) were
then synthesized with this core. Both retained potent IRAK4
inhibitory activity but 8 demonstrated better aqueous solubility,
pH 7.4 (14.6 μM), in comparison to 9 (<2 μM). As a proof of
this excellent IRAK4 inhibition, compound 8 also showed
excellent inhibition of LTA induced TNFα in THP-1 cells.
Given such good translation of enzymatic to cellular potency,
some additional modifications were explored on 8 to lower
cLogDpH7.4, and in the process, different modifications around
the gatekeeper, Lys213-Asp329, and ribose pockets were
designed. Among the different gatekeeper modifications ex-
plored (Table 2), 10 and 13−15 showed IRAK4 inhibition as
good as 8 but 11 and 12 with a bulkier pyridyl in between the
hydroxyl or amino pyrrolidine and hinge interacting moieties
showed somewhat inferior inhibition likely due to steric
interference of the terminal hydroxyl and primary amine
respectively with the positively charged Lys213. Out of these,
13 and 15 turned out to be the best taking into account both
cLogDpH7.4 and target inhibition. Although 14 also showed
IRAK4 inhibition as good as 13 and 15 but cLogDpH7.4 was
observed to be somewhat inferior (Table 2).
At this stage we chose these two gate-keeper region moieties
and proceeded to explore SAR in the ribose pocket. A small
library of analogs was synthesized taking these two chosen gate-
keeper region moieties, and it was observed that polar and
nonpolar groups were tolerated in this region, which was helpful
for optimization of overall lipophilicity of these molecules.
Initially 16 and 17 with a small ribose pocket group (R2) but
different gate-keeper/back-pocket moieties (R1) were synthe-
sized (Table 3). Since 16 showed comparatively better IRAK4
inhibition, this gate-keeper/back-pocket moiety (2-methylpyr-
idine) was prioritized for further SAR generation. Compounds
16−25 (Table 3) were considered for in vitro ADME evaluation
in order to identify leads for in vivo studies. Based on the ADME
profile, we shortlisted compounds 24 and 25 as the most active
analogs (IRAK4 IC50 < 30 nM) having reasonable solubility,
good permeability, and desirable microsomal stability across
tested species. Both of these enantiomeric analogs 24 and 25
showed good LTA induced TNFα inhibition in THP-1 cells
a
Calculated using MarvinView6.1.7.
arthritis and hidradenitis suppurativa.17,18 Apart from PF-
06650833, four other compounds have also entered clinical
development during the past few years and are currently in phase
1 trials, viz., BAY-1830839,19 BAY-183484520 (Bayer), R-83521
(Rigel), and our chemical matter, CA-494822 (Figure 1). The
Bayer and Rigel compounds are currently under evaluation for
treatment of autoimmunity, inflammation, psoriasis, and ABC-
DLBCL21,23,24 whereas CA-4948 is being tested in patients with
relapsed or refractory hematologic malignancies including non-
Hodgkin lymphoma, MDS, and AML.22 Herein, we disclose the
design strategies and SAR optimization that led to identification
of CA-4948.
The in-house kinase focused library screening campaign at
Aurigene resulted in identification of a few moderately potent
IRAK-4 inhibitors. Among these, the cocrystal structure of an
early benzoxazole amide hit (1) in complex with IRAK4 revealed
the binding mode and critical active-site interactions of this class
of compounds (Figure 2a). The amide carbonyl was observed to
be the kinase hinge interacting moiety, and the benzoxazole
oxygen was noticed to be within modest hydrogen bonding
distance (3.4 Å) from Tyr264 in the same region. Apart from
these, the bipyridyl appendage connected to the amide was
found to be occupying a region close to the gatekeeper residue
Tyr262 with the distal 4-pyridyl making a hydrogen bonding
interaction with catalytic Lys213. Comparison with the binding
mode of AMP-PNP in IRAK4 led to the identification of several
potential design opportunities in order to improve the binding
affinity of 1, e.g., by optimizing the interactions around Lys213,
occupying the ribose pocket, etc. (Figure 2a). Therefore, a few
analogs (2−5) were synthesized based on this strategy and
interestingly all these compounds showed significant improve-
ment in target inhibition with respect to 1, thereby validating
these hypotheses. Out of these, 4 and 5 with ribose pocket
extensions showed significantly improved target inhibition by
over 150-fold. Among these, 5 showed IRAK4 IC50 < 5 nM and
C
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Table 3. Ribose Pocket Modification of Compounds 13 and 15
a
b
Calculated using MarvinView6.1.7. Shown as IC50 standard deviation (N = 4).
Table 4. Percentage Inhibitions Measured for Key Compounds in Table 3 against Different Kinases in-House
FLT3
CDK2
AURA
GSK3B
MUSK
a
a
a
a
a
a
a
a
a
a
ID
0.1 μM
1.0 μM
0.1 μM
1.0 μM
0.1 μM
1.0 μM
0.1 μM
1.0 μM
0.1 μM
1.0 μM
19
22
24
25
87
82
42
34
94
92
70
64
44
20
0
81
69
10
15
3
0
0
6
19
13
0
46
47
0
86
84
6
14
13
0
28
18
4
9
5
12
16
7
10
a
Indicates compound concentration.
(IC50 514 and 233 nM, respectively). However, 24 was found to
be superior to 25 both in terms of selectivity in a small in-house
kinase panel (Table 4) as well as in mouse PK (Table 5). 24
showed better clearance as well as AUC than 25, and moreover
the excellent oral PK profile of 24 across preclinical species
(Table 5) encouraged us to consider 24 for further evaluation.
A cocrystal structure of 24 in complex with IRAK4 was
resolved where the binding mode was observed to be similar to
D
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a
Table 5. Pharmacokinetic Properties of 24 and 25
Dose
(mg/kg)
C0 (ng/ AUC0‑t (h × ng/
VD
CL
T1/2
(h)
Cmax
(ng/mL)
AUC0‑t
(h × ng/mL)
Tmax
(h)
Compound Species
Route
mL)
mL)
(mL/kg) (mL/h/kg)
%F
24
25
24
25
24
24
24
24
Mice
3
iv
7482
788
5274
928
661
5573
556
3134
2.6
0.8
10
po
6618
2531
12464
4489
0.5
0.3
71
100
Rat
3
10
1
iv
po
iv
27659
1963
111567
6064
2000
500
24
5.3
2.6
22147
171258
86465
1.2
46
Dog
186
10
po
12823
1.17
100
a
Values represented as mean with sparse sampling technique. iv formulation (solution) includes 10% v/v ethanol, 30% v/v PEG, and 60% v/v
water. po formulation (suspension) contains 50 parts of 1% v/v Tween 20 in water and 50 parts of 0.5% w/v hydroxy ethyl cellulose.
Table 6. IL-6 Release Inhibition Observed with 24 under
Different Stimulation Conditions in Whole Blood Assays
(≥50% inhibition at 1 μM) in a handful of other kinases such as
CLK1, CLK2, CLK4, FLT3, DYRK1A, DYRK1B, TrkA, TrkB,
Haspin, and NEK11. The compound also showed good
modulation of IL6 in human whole blood assay (Table 6) and
pIRAK1 modulation (IC50 of 270 nM) in MV4-11 cell-line, as
cellular proof of mechanism. 24 when screened in cellular
growth inhibition assay in a short panel of lymphoma cell lines
demonstrated moderate potency in OCI-Ly10 (IC50 = 1.5 μM)
harboring MYD88 mutation.
a
Stimulation Condition for IL-6 release
IC50 (nM)
TLR2 (LTA) induced
IL-1R (IL-1β) induced
TLR5 (FLA-ST) induced
989 686 (N = 3)
1375 272 (N = 2)
696 (N = 1)
a
Blood from different donors was used in each experiment/each
replicate. IC50 values are represented as mean
applicable.
SD wherever
In vivo efficacy of 24 was evaluated in an OCI-Ly3 xenograft
model through oral route of administration in a once daily
dosing regimen (Figure 3). A dose of 200 mg/kg q.d. showed
partial tumor regression and a 100 mg/kg q.d. dose showed
>90% tumor growth inhibition. The compound was well-
tolerated, and there were no overt toxicities at these efficacious
doses. Drug concentrations from plasma and tumors were
determined at 2 h post final dose administration on day 15.
Compound 24 treatment resulted in dose proportional increase
in plasma and tumor exposures (Table 7). Activated TLR/IL1R
results in the assembly of the Myddosome, a multiprotein
complex composed of MyD88, IRAK4, and IRAK2 proteins.
Myddosome protein complex activates the serine/threonine
kinase, IRAK1, through IRAK4-dependent phosphorylation;
therefore, we monitored phosphorylation of IRAK1 as a PD
marker of IRAK4 inhibition.2,3,25 In a PK-PD study in OCI-Ly3
tumor bearing animals (Figure 4), 24 (200 mg/kg) showed 78%
and 56% inhibition of pIRAK1, respectively, in tumor tissues at
12 and 24 h, respectively (Figure 4a), which correlated well with
observed plasma and tumor exposures at these time-points
(Figure 4b). Low pIRAK1 exposures observed at 4 and 8 h time-
points (Figure 4b) likely due to IRAK1 being downstream in
MYD88-IRAK signaling hence taking more time for demon-
strating modulation of pIRAK1. Similar observations were noted
in in vitro experiments wherein pIRAK1 modulation was
observed only at later time points (data not shown). 24 also
exhibited good CYP inhibition profile (IC50 > 50 μM in
CYP2C19 and <5% inhibition at 1 μM across CYP3A4, 2D6,
2C9, 2C8, 2B6, and 1A2) and microsomal stability in mouse, rat,
and human. 24 was not genotoxic in the in vitro bacterial
mutagenesis assay and did not produce any biologically relevant
clastogenicity changes in the in vivo micronucleus test in mice.
Based on its overall profile including efficacy and desirable
tolerability in toxicology studies in both mouse and dog, 24 was
advanced into clinical development26 and later code-named CA-
4948.
Figure 3. In vivo efficacy of 24 in OCI-Ly3 xenograft model. One-way
ANOVA, Dunnett’s multiple comparison’s test: **p < 0.01, ****p <
0.0001.
Table 7. Mean Plasma and Tumor Concentrations of
Compound 24 after Repeated Oral Administration in OCI-
Ly3 Tumor Bearing Mice
Treatment groups Mean plasma conc (ng/mL) Mean tumor conc (ng/g)
25 mg/kg
50 mg/kg
100 mg/kg
200 mg/kg
5077.8 587.5
11565.9 1074.7
23268.2 2280.2
39123.0 3101.2
2667.2 399.7
8291.2 1013.3
17943.3 2122.6
36973.7 2622.5
that of 1. Nevertheless, the Lys213 and Tyr264 polar contacts
observed in the case of 1 were found to be absent here, and
instead this compound was observed to be making a water
mediated contact from the hydroxy group with Glu194
backbone and a direct Asp329 backbone interaction with the
pyridyl nitrogen (Figure 2b). 24 was further evaluated in a broad
kinome panel (Eurofins, 329 kinase). Apart from IRAK4, this
compound was also observed to be exhibiting significant activity
24 (CA-4948) was synthesized starting with 2-chloro-5-
hydroxy pyridine (I) which was nitrated with nitrating mixture
followed by reduction with Raney Ni to get compound III
E
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Figure 4. In vivo PK/PD of 24 showing (a) pIRAK1 modulation and (b) plasma−tumor exposures. Mean mPPB of 24 = 92.8% (Average of 2
determinations). Unbound plasma exposures at 12 and 24 h estimated to be 868.0 and 49.3 ng/mL, respectively.
Scheme 1. Synthetic Route of 24 (CA-4948)
(Scheme 1). Compound III was cyclized with potassium ethyl
xanthate followed by methylation of thiol to yield compound V
which was refluxed with morpholine to obtain compound VI.
Compound VI was nitrated with nitrating mixture to obtain
compound VII which was coupled with (R)-3-hydroxy
pyrrolidine to obtain compound VIII. Compound VIII was
reduced with Raney Ni followed by HATU coupling with
intermediate E resulting in CA-4948. Other compounds
described here were synthesized using similar procedures
described in the Supporting Information.
In conclusion, we have optimized a series of aza-benzoxazoles
and identified a compound demonstrating potent IRAK4
inhibition with favorable selectivity over other kinases, cellular
activity, pharmacokinetics, efficacy, and safety. The lead
compound, CA-4948 (24), showed tumor regression in a
rodent DLBCL xenograft model (OCI-Ly3) without any overt
toxicities. In a PK-PD study it also showed significant inhibition
of pIRAK1 which correlated well with plasma and tumor
exposures. While 24 showed significant inhibition of a few other
kinases (Table S1), there is no explicit literature evidence to
support contribution of such effects toward the observed efficacy
and pIRAK1 modulation. CA-4948 is currently being evaluated
in phase-1 clinical trials, in patients with Relapsed or Refractory
Hematologic Malignancies including non-Hodgkin lymphoma,
MDS, and AML.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00255.
■
sı
Experimental details for synthesis, protein expression,
assay methods, modeling, and crystallography (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Susanta Samajdar − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India; orcid.org/0000-0002-3508-
4801; Phone: +91 80 7102 5320; Email: susanta_s@
aurigene.com; Fax: +91 80 2852 6285
Authors
Venkateshwar Rao Gummadi − Aurigene Discovery
Technologies Ltd., Bangalore 560 100, India
Anima Boruah − Aurigene Discovery Technologies Ltd.,
Hyderabad 500 049, India
Bharathi Raja Ainan − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
Brahma Reddy Vare − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
Srinivas Manda − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
Hari Prakash Gondle − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
F
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survival of lymphoplasmacytic cells by activation of Bruton tyrosine
Shiva Nagendra Kumar − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
Subhendu Mukherjee − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
Suraj T. Gore − Aurigene Discovery Technologies Ltd., Bangalore
560 100, India
Narasimha Rao Krishnamurthy − Aurigene Discovery
Technologies Ltd., Bangalore 560 100, India
Sivapriya Marappan − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
̈
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Shilpa S. Nayak − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
Kavitha Nellore − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
Wesley Roy Balasubramanian − Aurigene Discovery
Technologies Ltd., Bangalore 560 100, India
Archana Bhumireddy − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
Sanjeev Giri − Aurigene Discovery Technologies Ltd., Bangalore
560 100, India
Sreevalsam Gopinath − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
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Girish Daginakatte − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
Aravind Basavaraju − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
Shekar Chelur − Aurigene Discovery Technologies Ltd., Bangalore
560 100, India
Rajesh Eswarappa − Aurigene Discovery Technologies Ltd.,
Hyderabad 500 049, India
Charamanna Belliappa − Aurigene Discovery Technologies Ltd.,
Bangalore 560 100, India
Hosahalli S. Subramanya − Aurigene Discovery Technologies
Ltd., Bangalore 560 100, India
Robert N. Booher − Curis Inc., Lexington, Massachusetts 02421,
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Murali Ramachandra − Aurigene Discovery Technologies Ltd.,
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Pink, J. H.; Robb, G. R.; Rosen, A.; Shen, M.; McWhirter, C.; Wu, D.
Discovery and Optimization of Pyrrolopyrimidine Inhibitors of
Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment
of Mutant MYD88L265P Diffuse Large B-Cell Lymphoma. J. Med.
Chem. 2017, 60, 10071−10091.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.0c00255
(13) Lee, K. L.; Ambler, C. M.; Anderson, D. R.; Boscoe, B. P.; Bree, A.
G.; Brodfuehrer, J. I.; Chang, J. S.; Choi, C.; Chung, S.; Curran, K. J.;
Day, J. E.; Dehnhardt, C. M.; Dower, K.; Drozda, S. E.; Frisbie, R. K.;
Gavrin, L. K.; Goldberg, J. A.; Han, S.; Hegen, M.; Hepworth, D.; Hope,
H. R.; Kamtekar, S.; Kilty, I. C.; Lee, A.; Lin, L. L.; Lovering, F. E.;
Lowe, M. D.; Mathias, J. P.; Morgan, H. M.; Murphy, E. A.;
Papaioannou, N.; Patny, A.; Pierce, B. S.; Rao, V. R.; Saiah, E.;
Samardjiev, I. J.; Samas, B. M.; Shen, M. W. H.; Shin, J. H.; Soutter, H.
H.; Strohbach, J. W.; Symanowicz, P. T.; Thomason, J. R.; Trzupek, J.
D.; Vargas, R.; Vincent, F.; Yan, J.; Zapf, C. W.; Wright, S. W. Discovery
of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-
2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-
06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor
Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design. J. Med.
Chem. 2017, 60, 5521−5542.
Notes
The authors declare the following competing financial
interest(s): All authors are current or former employees of
Aurigene Discovery Technologies Limited or Curis Inc.
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