Discovery of Potent and Selective 7-Azaindole Isoindolinone-Based PI3KγInhibitors

Article abstract of DOI:10.1021/acsmedchemlett.0c00387

The successful application of immunotherapy in the treatment of cancer relies on effective engagement of immune cells in the tumor microenvironment. Phosphoinositide 3-kinase γ(PI3Kγ) is highly expressed in tumor-associated macrophages, and its expression levels are associated with tumor immunosuppression and growth. Selective inhibition of PI3Kγoffers a promising strategy in immuno-oncology, which has led to the development of numerous potent PI3Kγinhibitors with variable selectivity profiles. To facilitate further investigation of the therapeutic potential of PI3Kγinhibition, we required a potent and PI3Kγ-selective tool compound with sufficient metabolic stability for use in future in vivo studies. Herein, we describe some of our efforts to realize this goal through the systematic study of SARs within a series of 7-azaindole-based PI3Kγinhibitors. The large volume of data generated from this study helped guide our subsequent lead optimization efforts and will inform further development of PI3Kγ-selective inhibitors for use in immunomodulation.

Full text of DOI:10.1021/acsmedchemlett.0c00387

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Letter
Discovery of Potent and Selective 7-
Azaindole Isoindolinone-Based PI3K# Inhibitors
Dillon H. Miles, Xuelei Yan, Rhiannon Thomas-Tran, Jeremy Fournier, Ehesan U. Sharif, Samuel L.
Drew, Guillaume Mata, Kenneth V. Lawson, Elaine Ginn, Kent Wong, Divyank Soni, Puja Dhanota,
Stefan G. Shaqfeh, Cesar Meleza, Ada Chen, Amber T. Pham, Timothy Park, Debbie Swinarski,
Jesus Banuelos, Ulrike Schindler, Matthew J. Walters, Nigel P. Walker, Xiaoning Zhao, Stephen
W. Young, Jie Chen, Lixia Jin, Manmohan Reddy Leleti, Jay P. Powers, and Jenna L. Jeffrey
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.0c00387 • Publication Date (Web): 24 Sep 2020
Downloaded from pubs.acs.org on September 25, 2020
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Title: Discovery of Potent and Selective 7‑Azaindole Isoindolinone-Based PI3K Inhibitors
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Author Names: Dillon H. Miles, Xuelei Yan, Rhiannon Thomas-Tran, Jeremy Fournier, Ehesan U. Sharif,
Samuel L. Drew, Guillaume Mata, Kenneth V. Lawson, Elaine Ginn, Kent Wong, Divyank Soni, Puja Dhanota,
Stefan G. Shaqfeh, Cesar Meleza, Ada Chen, Amber T. Pham, Timothy Park, Debbie Swinarski, Jesus Banuelos,
Ulrike Schindler, Matthew J. Walters, Nigel P. Walker, Xiaoning Zhao, Stephen W. Young, Jie Chen, Lixia Jin,
Manmohan Reddy Leleti, Jay P. Powers, and Jenna L. Jeffrey*
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Author Address: Arcus Biosciences, Inc., Hayward, CA 94545, United States
Abstract: The successful application of immune checkpoint therapy in the treatment of cancer relies on effective
engagement of immune cells in the tumor microenvironment. Phosphoinositide 3-kinase  (PI3K) is highly
expressed in tumor-associated myeloid cells and its expression levels are associated with tumor
immunosuppression and growth. Selective inhibition of PI3K offers a promising strategy to render tumors more
responsive to immunotherapy, which has led to the development of numerous potent PI3K inhibitors with
variable selectivity profiles. To facilitate further investigation of the therapeutic potential of PI3K inhibition, we
required a potent and PI3K-selective tool compound with sufficient metabolic stability for use in future in vivo
studies. Herein, we describe our efforts to realize this goal through the systematic study of SARs within a series
of 7-azaindole-based PI3K inhibitors. The large volume of data generated from this study helped guide our
subsequent lead optimization efforts and will inform further development of PI3K-selective inhibitors for use in
immunomodulation.
Keywords: PI3K, inhibitor, selective, azaindole, immunomodulation, cancer
Phosphoinositide 3-kinases (PI3Ks) are a class of enzymes responsible for the regulation of a wide variety of
cellular activities such as signaling, survival, metabolism, and transport. A common substrate of these kinases is
the glycerophospholipid phosphatidylinositol (PIP): PI3K-mediated phosphorylation of PIP initiates a signaling
cascade via downstream proteins (e.g., protein kinase B (PKB), commonly referred to as Akt, and 3-
phosphoinositide-dependent protein kinase-1 (PDPK1)) and ultimately mediates critical cellular functions, such
as motility and proliferation.1,2 The class I PI3Ks, including PI3K, PI3K, PI3K, and PI3K, phosphorylate the
C3-hydroxyl group of the inositol ring in phosphatidylinositol 4,5-bisphosphate.3
Although PI3Ks are involved in a variety of functions and are expressed throughout the body, PI3K and PI3K
are of particular interest due to their expression in leukocytes as effectors of immune responses.4-7 In oncology,
abnormalities in PI3K expression have been linked to cancer development, corresponding to high levels of PI3K
expression and activity within immunosuppressive myeloid cells.8-18 Due to the significance of PI3K and PI3K
in immunomodulation, many inhibitors with varying degrees of selectivity have been developed for the treatment
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of cancers and other pathologies of the immune system.19, 20 Structures of several potent and -selective inhibitors
have been published, selected examples of which are shown in Figure 1a.21-27 Among these, 1 (IPI-549, Infinity
Pharmaceuticals) is the only -selective inhibitor currently in clinical trials (Ph. 1/2).28-32 Aryl sulfonamide 2
(developed by Exelixis), an advanced lead compound that resulted from optimization of a high-throughput
screening hit, exhibits high PI3K isoform selectivity but also inhibits the mammalian target of rapamycin (mTOR)
and other off-target kinases.25 Recently, researchers at AstraZeneca reported a series of aminothiazole-based
PI3K inhibitors such as 3, which was characterized by x-ray crystallography in complex with mouse PI3K
(PDB ID 6FTN).26, 27 The high isoform selectivity of 3 and its analogs was attributed to the ability of the
cyclopropylethyl group to displace the DFG motif of PI3K, which causes a unique  isoform-specific
conformational change.27
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As shown in Figure 1b using aryl sulfonamide 2 as a prototypical example, three regions exist within the ATP
binding pocket of PI3K, which are typically considered during inhibitor design.33 Interaction with the hinge
region is considered essential for inhibitor activity; most known inhibitors engage in at least one hydrogen bond
to V882. Inhibitor binding interactions within the affinity pocket are known to considerably influence both
potency and selectivity against the other PI3K isoforms, as communicated in the discovery of 3.26, 27 Most
inhibitors that bind within the affinity pocket possess a functional group that engages K833 via hydrogen bonding
or polar interactions. Finally, inhibitor binding within the specificity pocket also influences both potency and
selectivity, as demonstrated in the discovery of IPI-549.24 The W812 side chain in this region of the enzyme-
inhibitor complex is well-positioned for an edge-to-face interaction with the inhibitor’s planar motif, as confirmed
by the recently reported x-ray co-crystal structure of IPI-549 in complex with human PI3K (PDB ID 6XRL).35
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a)
H2N
O
N
N
F
N
H
N
O
S
H2N
N
F
1
N
2
3
4
5
O
O
NH
Me
NH
Cl
2 (ref. 25)
PI3K IC50 = 773 nM c
Me
Ph
N
O
c
690x selectivity over PI3K
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Me
N
HN
Me
S
Me
N
N
O
N
Me
O
Me
1 (IPI-549) (ref. 24)
PI3K IC50 = 20 20 nM a
3 (ref. 26, 27)
PI3K IC50 = 90 30 nM a
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b
390x selectivity over PI3K
b
491x selectivity over PI3K
V882
hinge region
b)
N
H
O
H2N
O
N
N
W812
HN
affinity pocket
NH
Me
Cl
Ar
S
O
O
K833
H3N
N
H
specificity pocket
Figure 1. a) Cellular potencies and biochemical selectivity values of PI3K-selective inhibitors (see SI for a comparison of literature
a
and. in-house assay protocols). Determined in-house using the AlphaLISA SureFire Ultra Akt assay (PerkinElmer) with THP-1 cells.
bDetermined in-house using the ADP-Glo Lipid Kinase assay (Promega) with 25 M ATP and 50 M phosphatidylinositol 4,5-
bisphosphate as substrate. Reported ATP Km = 29 ± 3.7 M.34 cPublished value. b) Schematic of typical inhibitor binding modes within
PI3K, exemplified by 2.25
Considering the promise of selective PI3K inhibition for cancer immunotherapy, we pursued the design of novel
inhibitor structures, utilizing the extensive body of medicinal chemistry knowledge as a source of inspiration. Our
primary objective was to design a molecule possessing 1) similar or greater PI3K inhibitory potency and isoform
selectivity compared to known inhibitors, such as 1, as measured in both biochemical and cell-based PI3K
inhibition assays, and 2) suitable ADME properties for use in future in vivo studies. A molecule fulfilling these
criteria would enable the eventual deconvolution and appreciation of the role of PI3K inhibition in the context
of our broader immunomodulatory work. To realize these goals, we embarked upon the discovery of novel
inhibitors, initially through a pharmacophore mapping approach based on visual comparison of known literature
inhibitors followed by a systematic SAR investigation of promising lead molecules, some of which have recently
been described.35
Due to the high isoform selectivity and potency of 3 (4 ± 1 nM, as determined in our in-house biochemical assays,
which measure a compound’s ability to inhibit the kinase activity of PI3K; see SI for details) and its analogues,26,27
we designed an initial set of compounds by attempting to mimic the hinge-binding acylaminothiazole moiety with
a variety of functionally similar heterocycles (Table 1). Most of the compounds investigated contained both a
hydrogen bond donor and a hydrogen bond acceptor motif, which could potentially create a stronger interaction
with V882. We initiated our studies with racemic compounds 4 and 5, which bear a structural resemblance to 3.
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Although potency was substantially reduced for these compounds (IC50 = 0.6 M and 0.53 M, respectively), we
were encouraged by the fact that replacement of the aminothiazole motif did not eliminate activity. Although
triazolopyridine 6 showed decreased potency (IC50 = 1.6 M), a less acidic analogue, (±)-7, was significantly
more active (IC50 = 0.09 M). In contrast, an isomeric analogue, 8, in which the pyrazole NH group is not properly
positioned for interaction with V882, was significantly less potent (IC50 = 0.49 M), confirming the importance
of a hydrogen bond donor and acceptor pair for interaction with the hinge region. The stereochemical
configuration of these compounds was also shown to be important, as 7, the (S) enantiomer of (±)-7, showed
improved activity (IC50 = 0.035 M) compared to the racemic compound. Although enantiopure pyrazolopyrazine
9 showed a 2-fold reduction in potency (IC50 = 0.08 M) relative to 7, azaindole 10 (IC50 = 0.05 M) had similar
inhibitory activity to 7.
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Based on these results and earlier studies by the Meng and Zhou labs,36 we evaluated the incorporation of a 4-
pyridyl moiety at the C3 position of the two most promising scaffolds (i.e., azaindazole 7 and azaindole 10),
which we envisioned would provide favorable interactions with the specificity pocket of PI3K. Consistent with
our hypothesis, azaindazole 11 (IC50 = 8 nM) was 4-fold more potent against PI3K than 7, while azaindole 12
(IC50 = 3.4 nM) showed an even greater improvement in potency (approximately 15-fold) relative to the
unsubstituted analogue, 10. (R)-12 was 3-fold less potent than 12, consistent with the previously reported
superiority of the (S) enantiomer of the isoindolinone moiety of 3.25 These initial studies established 12 as a
suitable starting point for further optimization.
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Table 1. Modification of the Hinge-Binding Region
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aIC50 values measured using the ADP-Glo Lipid Kinase Assay (Promega) with 25 M ATP and 50 M phosphatidylinositol 4,5-
bisphosphate as substrate. bCompound was tested once.
Our subsequent efforts centered on evaluation of various C3-substituted derivatives of 12 (Table 2). To better
distinguish between compounds that generally displayed low-nanomolar potency in the biochemical kinase
activity assay, we further characterized these inhibitors under more physiologically relevant conditions using a
functional cellular inhibition assay, which measures the extent of PI3K-mediated phosphorylation of Akt. To
assess PI3K isoform selectivity, we employed routine enzymatic kinase activity assays for the  and  PI3K
isoforms only, as most of the compounds in this series were inactive against the  isoform at concentrations up
to 10 M (>1,000-fold selectivity). We were pleased to find that compound 12 exhibited sub-micromolar activity
in THP-1 cells (THP-1 IC50 = 0.22 M), with excellent isoform selectivity (379-fold vs. PI3K and 290-fold vs.
PI3K). The observed difference between biochemical and cellular potency was not surprising, as cellular potency
is frequently impacted by a compound’s permeability, protein binding and off-target activity, as well as
differences in the concentration of ATP present under the assay conditions.
Although the 3-pyridyl analogue 13 (IC50 = 7 nM, THP-1 IC50 = 0.4 M) showed comparable potency to 12, the
2-pyridyl analogue (14) was substantially less active (IC50 = 33 nM, THP-1 IC50 = 3.5 M), indicating a hydrogen
bond acceptor extending outward from the core is advantageous.37 Other modifications preserving this paradigm
(e.g., 15-19) were either tolerated or had reduced activity, with biochemical potency values ranging from 2.6 to
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42 nM, and THP-1 cell potencies ranging from 0.20 to 3.5 M. Pyrazole 20 (IC50 = 3.3 nM, THP-1 IC50 = 0.2
M) showed comparable potency to 12, but incorporation of a saturated, basic amine substituent (e.g., 21, IC50 =
281 nM, THP-1 IC50 = 3.8 M) proved to be detrimental to activity. Interestingly, carboxylic acid 22 and its
amide derivatives, 23 and 24, were moderately active in the biochemical assay (IC50 = 13 nM, 12 nM, and 4.5
nM, respectively) despite being structurally distinct, although cellular potencies were more variable (THP-1 IC50
= 11 M, 1.3 M, and 0.32 M, respectively).
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In addition to 5- and 6-membered aromatic heterocycles, benzoic acids were identified as suitable C3 substituents.
para-Benzoic acid 25 (IC50 = 2.5 nM, THP-1 IC50 = 0.14 M), as well as several substituted benzoic acid
analogues (26-30 and 33-35), exhibited improved cellular potency compared to 20. The ortho-methyl, -isopropyl,
and -cyclopropyl analogues of 25 showed an encouraging increase in cellular potency (THP-1 IC50 = 0.078 M,
0.059 M, and 0.040 M, respectively). Disubstituted analogues of 25 (e.g., 29 and 30, THP-1 IC50 = 0.09 M
and 0.07 M, respectively), for which steric effects limit the conformational freedom of the carboxylate group
and may attenuate productive interactions within the affinity pocket, showed a minimal reduction in potency
relative to the mono-substituted counterparts. Electron-poor benzoic acid derivatives (e.g., 31 and 32, THP-1 IC50
= 0.7 M and 0.35 M, respectively), showed a substantial decrease in potency, while analogues bearing electron-
donating methoxy or pyrrolidine ortho-substituents (e.g., 33 and 34, THP-1 IC50 = 0.17 M for both) showed
similar potency to unsubstituted benzoic acid 25.
Interestingly, while meta-benzoic acid 35 (THP-1 IC50 = 0.11 M) exhibited similar potency to the para-analogue
(25), introduction of an ortho-methyl substituent to 35 resulted in a two-fold reduction in potency (36, THP-1
IC50 = 0.26 M). This observation further corroborates the potential effect of the conformation of the carboxylate
group on compound potency. In contrast to 25 and 35, ortho-benzoic acid derivative 37 exhibited a dramatic
reduction in potency (THP-1 IC50 = 15 µM), consistent with the trends observed for isomeric pyridine analogues
12-14. Amide and sulfonamide analogues of 25 generally exhibited reduced potency (38 and 39, THP-1 IC50 =
0.23 M and 0.40 M, respectively). For the compounds shown in Table 2, cellular potencies generally correlated
with biochemical potency. Apart from compounds with a particularly unique geometry (21, 22, and 37), a modest
correlation was observed between cellular potency and biochemical assay-derived lipophilic efficiency values
(see SI for details). Although there was substantial variation of isoform selectivity among the assayed compounds,
most of the active compounds exhibited >100-fold selectivity against both PI3K and . The highest isoform
selectivity was observed for amide 24 and benzoic acid analogues 29 and 36.
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Table 2. Evaluation of Azaindole C3 Substituents
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aEnzymatic kinase activity assay. Ratio of PI3K or PI3K enzymatic inhibition over PI3K inhibition. Cellular potency in THP-1
cell line. dRacemate. eCompound was tested once.
During the course of these investigations into the SAR of the C3 substituent, we also concurrently investigated
the SAR of the N2’ isoindolinone substituent of 12 (selected due to its combination of potency, selectivity and
structural simplicity), which we envisioned would be situated within the affinity pocket of the PI3K-inhibitor
complex (Table 3). Replacement of the methyl group of the cyclopropylethyl moiety with either an ethyl group
(40, IC50 = 6 nM, THP-1 IC50 = 0.8 M) or a cyclopropyl group (41, IC50 = 6.8 nM, THP-1 IC50 = 0.8 M)
resulted in similar biochemical potency and selectivity but approximately 4-fold reduction in cellular potency. On
the other hand, replacement of the cyclopropyl group with a methoxymethylene group (see 42, IC50 = 9 nM, THP-
1 IC50 = 0.6 M) resulted in a 3-fold reduction in both biochemical and cellular potency and a substantial reduction
in isoform selectivity, confirming the important contribution of the cyclopropyl group to isoform selectivity. An
even greater reduction in potency and selectivity was observed for tetrahydropyran 43 (IC50 = 50 nM, THP-1 IC50
= 1.0 M), which reinforces the importance of the specific size and shape of the N-alkyl substituent. Analogues
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bearing a sterically bulky N-alkyl substituent, such as a t-butyl group (44, IC50 = 26 nM, THP-1 IC50 = 0.72 M),
showed diminished potency and isoform selectivity. Similarly, reduced potency and selectivity were observed for
analogue 45 (IC50 = 28 nM), which bears an additional methyl group relative to 12 and is achiral. Despite its large
size, arylethane 46 retained modest activity in the biochemical assay (IC50 = 40 nM) but its potency in cells was
significantly decreased (THP-1 IC50 = 2.1 M) relative to 12. Compound 47 (THP-1 IC50 = 1.6 M), which bears
an unbranched trifluoroethyl group, exhibited a significant reduction in both potency and selectivity compared to
12. Taken together, these results indicated that proper substitution of the isoindolinone nitrogen is critical to
achieving high potency and selectivity. Moreover, these studies further supported the importance of the
cyclopropylethyl group to achieving the optimal balance of potency and isoform selectivity exemplified by 12.
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Table 3. Modification of the N2' Substituent
aEnzymatic kinase activity assay. bRatio of PI3K or PI3K enzymatic inhibition over PI3K inhibition. cCompound was tested once.
Further characterization of 12 revealed that it was a potent inhibitor of the major CYP isoforms (IC50 values for
the 1A2, 2D6, 2C9, 2C19, and 3A4 CYP isoforms were 0.7 µM, 2.0 µM, 0.3 µM, <0.1 µM, and 0.3 µM,
respectively), possibly due to pyridine-iron coordination. On the other hand, pyrazole 20, which lacks the pyridine
moiety, showed an improved CYP inhibition profile (IC50 values for the 1A2, 2D6, 2C9, 2C19, and 3A4 CYP
isoforms were 2.9 µM, 26 µM, 1.4 µM, 0.2 µM, and 0.8 µM, respectively). Based on its decreased CYP inhibition
and comparable cellular potency to 12, 20 was selected for further exploration of the isoindolinone substituent.
As shown in Table 4, improvement of cellular potency could be realized while maintaining isoform selectivity
through various steric and electronic modifications of the C7’ group of 20. Incorporation of a sterically bulky
isopropyl group (48, THP-1 IC50 = 0.3 M) had little impact on potency or selectivity. Similarly, incorporation
of an electron-donating methoxy group (49, THP-1 IC50 = 0.17 M) or electron-withdrawing chloro- or nitrile
groups (e.g., 50 and 51, THP-1 IC50 = 0.17 M for both) also had little effect on potency or selectivity.
Importantly, trifluoromethyl analogue 52 (THP-1 IC50 = 0.09 M exhibited a two-fold improvement in potency
over 20 while maintaining high isoform selectivity. While both acetamide isomers 53 and 54 had reduced activity
(THP-1 IC50 = 0.73 and 0.5 M, respectively) relative to 20, C7’-sulfonamide and -sulfone analogues exhibited
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up to a four-fold improvement in potency (55-58, THP-1 IC50 = 0.05-0.15 M). Despite the promising potency
of 55 and 58, these compounds exhibited extrahepatic clearance in rat models (6.0 and 4.5 L/h/kg, respectively),
which precluded their further progression.
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Table 4. Modification of the C7' Substituent of 20
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aEnzymatic kinase activity assay. Ratio of PI3K or PI3K enzymatic inhibition over PI3K inhibition. Cellular potency in THP-1
cell line.
Faced with the CYP inhibition liabilities of C3-pyridine analogues and the poor metabolic stability of the C3-
pyrazole series, we turned our attention to the C3-benzoic acid series, exemplified by analogues 25, 26 and 29
(Table 5). Benzoic acid 25 and the corresponding ortho-substituted analogue, 26, both exhibited poor in vitro
metabolic stability, as measured in human and rat hepatocytes, with rat intrinsic clearance (CLint) values 40
L/min/106 cells. While hepatocyte stability could be improved through the incorporation of an additional ortho
substituent on the benzoic acid moiety (29, rat CLint 2.0 L/min/106 cells), this compound exhibited extrahepatic
clearance in rat models (e.g., CL = 6.9 L/h/kg). While the C7’-CF3 analogs of 26 and 29 (see 59 and 60, THP-1
IC50 = 0.04 and 0.03 M, respectively) demonstrated improved potency—consistent with our previous
observations in the C3-pyrazole series—their metabolic stability was comparable to the C7’-Me analogues. The
poor in vitro/in vivo correlation for this series of compounds may be due to active efflux, as Caco-2 permeability
studies revealed parent compound 25 to have low permeability (Papp=1.07 x 10-6 cm/sec) and an efflux ratio of
46.6.
Finally, a breakthrough came with the synthesis of C3 phenylacetic acid derivatives 61 (THP-1 IC50 = 0.16 M)
and 62 (THP-1 IC50 = 0.15 M). Although these molecules showed somewhat diminished inhibitory activity
relative to the benzoic acids, they retained high isoform selectivity and displayed an encouraging improvement
in hepatocyte stability (rat CLint = 17 and 23 L/min/106 cells for 61 and 62, respectively). Moreover, compound
62 exhibited significantly lower in vivo clearance (CL=1.8 L/h/kg) relative to the benzoic acid analogues, which
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lack a methylene spacer. Gratifyingly, additional substitution of the -methine group of 61 (see 63-65, THP-1
IC50 = 0.11-0.18 M) resulted in further improvements in human hepatocyte stability without substantially
altering the potency or selectivity of these inhibitors. While this optimization campaign did not ultimately deliver
a compound suitable for further development, compound 64 emerged as the most promising inhibitor due to its
good cellular potency, excellent selectivity, and acceptable pharmacokinetic profile.
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Table 5. Further Characterization and SAR of C3 Benzoic Acid and Phenylacetic Acid Azaindole Derivatives
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aEnzymatic kinase activity assay. Ratio of PI3K or PI3K enzymatic inhibition over PI3K inhibition. Cellular potency in THP-1
cell line. dCompound was tested once. eNot determined.
The general synthetic routes used to access our azaindole/azaindazole inhibitors are shown in Scheme 1. The
overall sequence is highly modular and allows for the introduction of diversity in several independent steps.
Depending on the specific substrate, conditions such as the coupling partner, palladium catalyst, base, or solvent
may vary (see SI for details). In general, the respective coupling steps can be done in any order to facilitate SAR
exploration.
As shown in Scheme 1a, isoindolinone intermediates A and B are generated from methyl benzoate and primary
amine precursors. These can be coupled to a variety of heterocyclic aryl bromides to yield a variety of simple
inhibitors (4-10, 24). Alternatively, A or B can be coupled with elaborated intermediates as shown in Scheme 1b.
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This sequence proved particularly useful during SAR evaluation of isoindolinone substituents. Finally, Scheme
1c was utilized toward the end of the study when the identity of the isoindolinone group was largely established,
enabling rapid identification of promising C3 aryl substituents.
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Scheme 1. General Synthetic Routes to Azaindole-Based Inhibitorsa
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aReagents and conditions: (a) NBS, (PhCO2)2, CCl4, 80 °C; (b) RNH2, B(OH)3, K2CO3, ACN, r.t.; (c) B2pin2, (dppf)PdCl2, KOAc,
dioxane, 100 °C; (d) (dppf)PdCl2, Na2CO3, dioxane/H2O, 100 °C; then deprotection (conditions vary, see SI); (e) (dppf)PdCl2, Na2CO3,
dioxane/H2O, 80 °C; (f) RNH2, HATU, i-Pr2NEt, DMF, 40 °C; (g) NBS, CH2Cl2, r.t.; (h) ArB(OR)2, (dppf)PdCl2, Na2CO3, dioxane/H2O,
100 °C; TFA, r.t.; N,N-DMEDA, MeOH, 45 °C.
Traditionally, ligand interactions within the affinity and specificity pockets of PI3K have been thought to
independently affect potency and selectivity, respectively. In contrast, our SAR investigations demonstrate that
improvements in both metrics can be realized through careful design of inhibitors that are capable of occupying
both regions of the enzyme active site. Through systematic SAR analysis, we have discovered a series of novel,
potent, and selective azaindole-based PI3K inhibitors. These compounds exhibit cellular IC50 values as low as
0.040 M (28), while maintaining >300-fold levels of selectivity against all other class I PI3K isoforms. In further
inhibitor design iterations, C3 phenylacetic acid derivatives (e.g., 64) exhibited significantly improved
pharmacokinetic properties, helping pave the way for future biological studies. The volume of data generated in
this study will help expedite future campaigns toward potent and orally bioavailable PI3K inhibitors for potential
clinical applications.
ASSOCIATED CONTENT
Supporting Information: The Supporting Information is available free of charge on the ACS Publications
website: biological assay procedures and synthetic procedures and characterization of PI3K inhibitors.
AUTHOR INFORMATION
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Corresponding Author: Jenna L. Jeffrey – Arcus Biosciences, Inc., Hayward, CA 94545, United States; Email:
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jjeffrey@arcusbio.com
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Author Contributions: D.H.M. and J.L.J. wrote the manuscript; D.H.M., J.L.J., E.U.S., G.M., K.V.L., M.R.L.,
and J.P.P. edited the manuscript; J.L.J., X.Y., R.T.-T., J.F., E.U.S., D.H.M., G.M., S.D., K.V.L., M.R.L., and
J.P.P. contributed to inhibitor design; J.L.J., X.Y., R.T.-T., J.F., E.U.S., D.H.M., G.M., S.D., and K.V.L.
synthesized the inhibitors; E.G., K.W., D.S., P.D., T.P., D.S., J.C., and L.J. provided ADME support; S.G.S.,
C.M., A.C., X.Z., S.W.Y. provided biological assay support; A.P., U.S., and N.P.W. provided protein support.
All authors have given approval to the final version of the manuscript.
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Notes: All authors are current or former employees of Arcus Biosciences.
ABBREVIATIONS
SAR, structure–activity relationship; ATP, adenosine triphosphate; ADME, absorption, distribution, metabolism,
and excretion; CYP, cytochrome P450; NBS, N-bromosuccinimide; ACN, acetonitrile; r.t., room temperature (23
°C); pin, pinacolato; dppf, 1,1'-bis(diphenylphosphino)ferrocene; HATU, (1-[bis(dimethylamino)methylene]-1H-
1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; DMF, N,N-dimethylformamide; SEM, 2-
(trimethylsilyl)ethoxymethyl; TFA, trifluoroacetic acid; N,N-DMEDA, N,N-dimethylethane-1,2-diamine
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(37) The 2-pyridyl substituent may also differentially affect the electronics of the central core, potentially
decreasing the azaindole binding affinity to the hinge region of the enzyme.
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For Table of Contents Use Only:
Title: Discovery of Potent and Selective 7‑Azaindole Isoindolinone-Based PI3K Inhibitors
Author Names: Dillon H. Miles, Xuelei Yan, Rhiannon Thomas-Tran, Jeremy Fournier, Ehesan U. Sharif,
Samuel L. Drew, Guillaume Mata, Kenneth V. Lawson, Elaine Ginn, Kent Wong, Divyank Soni, Puja Dhanota,
Stefan G. Shaqfeh, Cesar Meleza, Ada Chen, Amber T. Pham, Timothy Park, Debbie Swinarski, Jesus Banuelos,
Ulrike Schindler, Matthew J. Walters, Nigel P. Walker, Xiaoning Zhao, Stephen W. Young, Jie Chen, Lixia Jin,
Manmohan Reddy Leleti, Jay P. Powers, and Jenna L. Jeffrey*
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