Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pKa Polar Moiety

Article abstract of DOI:10.1021/acsmedchemlett.5b00398

Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pK_a and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. These studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in cancer and other diseases.

Full text of DOI:10.1021/acsmedchemlett.5b00398

Letter
pubs.acs.org/acsmedchemlett
Design of Selective PAK1 Inhibitor G‑5555: Improving Properties by
Employing an Unorthodox Low‑pKa Polar Moiety
Chudi O. Ndubaku,*,†,⊥ James J. Crawford,*,† Joy Drobnick,† Ignacio Aliagas,† David Campbell,‡
Ping Dong,§ Laura M. Dornan,† Sergio Duron,‡ Jennifer Epler,† Lewis Gazzard,† Christopher E. Heise,†
Klaus P. Hoeflich,†,# Diana Jakubiak,† Hank La,† Wendy Lee,† Baiwei Lin,† Joseph P. Lyssikatos,†,○
Jasna Maksimoska,∥,∇ Ronen Marmorstein,∥ Lesley J. Murray,† Thomas O’Brien,† Angela Oh,†
Sreemathy Ramaswamy,† Weiru Wang,† Xianrui Zhao,† Yu Zhong,† Elizabeth Blackwood,†
and Joachim Rudolph†
†Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
‡Afraxis, Inc., 6605 Nancy Ridge Road, Suite 224, San Diego, California 92121, United States
§Shanghai ChemPartner, 576 Libing Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, PRC
∥Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, United States
S
* Supporting Information
ABSTRACT: Signaling pathways intersecting with the p21-
activated kinases (PAKs) play important roles in tumorigenesis
and cancer progression. By recognizing that the limitations of
FRAX1036 (1) were chiefly associated with the highly basic
amine it contained, we devised a mitigation strategy to address
several issues such as hERG activity. The 5-amino-1,3-dioxanyl
moiety was identified as an effective means of reducing pKa
and logP simultaneously. When positioned properly within the
scaffold, this group conferred several benefits including
potency, pharmacokinetics, and selectivity. Mouse xenograft
PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. These studies
concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1
function in cancer and other diseases.
KEYWORDS: Kinase inhibitor, oncology, hERG, pKa
Several PAK1 inhibitors have been described in the literature
over the past few years.5 These include PF-3578309,6 previously
in clinical trials but no longer progressing, and FRAX1036 (1,
Figure 1 and Table 1).5 To us, compound 1 (FRAX1036)
represented a good opportunity for further investigations due to
a combination of high potency and moderate kinase selectivity,
including selectivity over the group II PAKs. Crystal structures
and molecular modeling showed that the basic amine moiety of
this compound and related analogues is located in a region of the
protein that lacks any specific interaction. In order to improve the
binding interactions, and thereby increase the potency (and
perhaps selectivity) of this class of molecules, we compared it to
another PAK1 selective inhibitor that we reported recently (2,
Figure 1).7 In this prior series, we found that it was possible to
drive PAK1 potency and group II PAK selectivity5 through
appending a basic amine toward a different vector within the
protein, specifically directed at Asp393/Asn394, taking advant-
he p21-activated kinases (PAKs), which belong to the
Tsterile-20 (STE20) family of kinases, play important roles
in the regulation of key cellular phenomena including cell
migration, proliferation, and survival mechanisms.1 These
kinases are located downstream of extracellular signaling
molecules: integrins, receptor tyrosine kinases (RTKs), G-
Protein coupled receptors (GPCRs), and immediately after
specific GTPases (Rac1 and Cdc42). They mediate signal
transduction through a variety of effector enzymes, proteins, and
transcription factors implicated in tumorigenesis and tumor
progression.1,2 In particular, PAK1 gene amplification and
protein overexpression is associated with poor prognosis in
luminal breast cancer.3 Furthermore, it was shown recently that
combining a PAK1 inhibitor with docetaxel altered microtubule
organization, which reduced the duration of mitotic arrest and
increased the kinetics of apoptosis.4 As a result of these important
links to cancer, there has been significant interest in the
identification of potent and selective PAK1 inhibitors that are
suitable for clinical development for the treatment of breast
cancers as well as other tumor types.
Received: October 9, 2015
Accepted: October 31, 2015
© XXXX American Chemical Society
A
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Figure 1. Overlay of FRAX1036 (1) (magenta, PDB: 5DFP) and aminopyrazole (2)7 (yellow, PDB: 4ZY5) in complex with PAK1, indicating a vector
for improving potency by interacting with polar residues such as Asn394.
Table 1. FRAX1036 (1), SAR around Amine Group Transposition and “Head-Group” Changes
a
b
Biochemical measurements reported are the geometric mean of ≥2 separate determinations; LLE = pKi − cLogP. Cellular assay to determine the
c
inhibition of the phosphorylation of residue S298 of MEK1 in EBC1 cells. Calculated using MoKa software (version 1.1.0, Molecular Discovery).
d
Compounds were incubated with Madin−Darby canine kidney cells (MDCK) at 10 μM test concentration over 60 min; Papp is the rate of apical−
e
basolateral (A−B) flux with units ×10−6 cm/s. N.D. = not determined.
age of differing orientations of the DFG Asp motif between PAKs
1 and 4. From overlaying these structures, we postulated that a
better direction to install a basic amine extension from the core of
1 was through the pyridone nitrogen. We reasoned that
transposing the piperidine substituent from the aminopyrimidine
portion of the core to this pyridone could allow us to increase
potency of this pyridonopyrimidine class of molecules through
the formation of electrostatic interaction with several polar
residues in the ribose pocket of the kinase.
In going from FRAX1036 (1, Table 1) to the corresponding 2-
ethylamino-4-piperidinylmethyl compound 3 we observed a 3.5-
fold increase in potency (Ki = 6 nM). There was a corresponding
net increase in ligand lipophilic efficiency (LLE)8 of 1.5. We next
found that a simple linear amine extension could provide a
similar potency increase, as demonstrated by compound 4.
Furthermore, by extending the amino substituent by one atom in
going to 5, an additional potency gain of 3-fold (Ki = 1.9 nM) for
a net >11-fold increase relative to the starting point, FRAX1036
(1), was achieved. Investigation of the R3 “head-group”, which
binds in an induced open space near the Met344 gatekeeper, led
us to settle on the 5-methyl-2-pyridinyl group (in 6), which was
equipotent to the 5-methyl-2-pyrazinyl group but showed a slight
improvement in permeability (Papp) due to the decreased
polarity. This group was found to be superior to several other
heterocyclic alternatives investigated by us (data not shown).
Finally, we observed that the 2-MeNH left-hand side R1 group
(7) offered a suitable alternative to the 2-EtNH, with a slight
lowering of hERG channel inhibition. To us, this latter
modification represented an advantageous change despite the
small loss in potency (∼3-fold) since the LLE was maintained (cf.
B
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a
Table 2. PAK1 Inhibitors with Low pKa Extensions Towards the Ribose Pocket
a
b
See Table 1 for assay descriptions and abbreviations. Compounds were incubated with human liver microsomes for 1 h, and % remaining was
determined by LC−MS/MS analysis.
The next question we addressed was whether we required such
basic amines (i.e., with calculated pKa > 10)9 to achieve the
observed level of potency. In particular, we were concerned that
high pKa when coupled with high cLogP would lead to greater
activity against ion channels, such as the hERG voltage-gated
potassium channel.10 This liability can often be mitigated by
reducing the pKa of a molecule or by reducing its lip-
ophilicity,11,12 and sometimes, greater reductions can be
achieved if both properties are reduced simultaneously.13,14
Indeed, we found compound 1 to show strong hERG inhibition
(89%) when tested at 10 μM in a patch clamp assay (Table 1).
Another issue with this initial set of compounds was that
permeability, measured using Madin−Darby canine kidney
epithelial cells (MDCK), was poor (e.g., Papp = 1.2 × 10−6 cm/
s for 6). Overall, these compounds clearly lacked the required
levels of permeability to achieve good cellular activity and oral
absorption.
We set out to address these concerns by reducing both the pKa
and the lipophilicity of our molecules (Table 2). Again, we
focused on the R2 amine-containing portion of the molecule that
binds within the ribose pocket of PAK1. Removing the basic
amine moiety (Table 2, compounds 8 and 9) resulted in a
dramatic reduction in biochemical activity and a corresponding
activity drop in the mechanistic cellular assay (in this case,
measuring phosphorylation levels of a PAK1-specific down-
Figure 2. Co-crystal structure of G-5555 (12) in complex with PAK1
(PDB: 5DEY). Hydrogen-bonding interactions are shown as dotted red
lines. Water molecules appear as red spheres.
5 and 7). It was clear that an amine moiety was able to drive
potency, presumably by interacting with the negatively charged
or polar oxygen residues (e.g., Asp393, Asn394, and Asp407) in
this region of the kinase. This polar pocket normally
accommodates the ribose sugar portion of the endogenous
substrate, ATP.
C
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Figure 3. Selectivity profile of compound 12. (A) Kinome tree diagram illustrating its kinase selectivity determined at 0.1 μM (Invitrogen). IC50 values
shown for kinases inhibited >70% other than PAK3 (IC50 not determined). (B) Bar chart illustrating the number of off-targets of 12 determined in a
secondary pharmacology screening panel (compound concentration = 10 μM). Green, inhibition <50%; yellow, inhibition between 50 and 75%; red,
inhibition >75%. The numbers indicate the counts contained within each bin. See Supporting Information for more details.
amines is through the inductive effects of oxygen atoms placed in
close proximity to the nitrogen. We saw that employing the R2
morpholine extension in 10 (calculated pKa = 6.9) resulted in
reasonable biochemical potency (Ki = 19 nM), albeit still
showing weak activity in cells (pMEK IC50 = 399 nM).
Reassuringly, the permeability of this compound was improved
(Papp = 3.5 × 10−6 cm/s), and the hERG activity was reduced
(21% inhibition at 10 μM test concentration). Next, an atypical
5-amino-1,3-dioxanyl moiety (compound 11, Table 2) was
introduced, which served to mimic the highly potent 4-
aminocyclohexane in compound 5 in Table 1. Although 1,3-
dioxanes are not commonly found in active pharmaceutical
agents due to their perceived instability, our choice to use this
particular group was inspired by the fact that the proximal amine
group serves to “protect” the sensitive acetal functionality against
protonolysis.15,16 Through adding two geminal oxygen atoms the
substituent remains meso, thereby minimizing stereochemical
complexity. Furthermore, the inductive effect of having two
oxygen atoms β to the amine has the benefit of reducing its
basicity to a desirable range (calculated pKa = 7.7 for 11). Finally,
the clogP of this analogue was reduced by greater than two units.
Due to a valid concern about the stability of such a group, we
undertook a series of forced degradation experiments with 11
and found this compound to be stable.17 Additionally, the in vitro
stability in liver microsomes was comparable to (or better than)
previous compounds evaluated (HLM CLhep = 9.6 mL/min/kg).
To build upon the advantages offered by 11, we sought to
improve upon its permeability and cellular potency.
Figure 4. Concentration−time curve of 12 dosed i.v. (2 mg/kg) or p.o.
(25 mg/kg). Each curve represents mean values measured for three
mice.
To this end, some of the features that previously had been
shown to be beneficial were introduced to this molecule. This
included refinement of the left-hand side group to a 2-MeNH
group (instead of 2-EtNH) and the right-hand side to a
methylpyridine (replacing the methylpyrazine). These efforts led
to the identification of compound 12 (G-5555), which was
potent, showing good activity in the pMEK cellular assay, had
improved permeability, and importantly, displayed low hERG
channel activity (<50% inhibition at 10 μM).17,18 N-Methylation
of the amino group (13) in an attempt to further increase
permeability by reducing H-bond donors did not provide any
Figure 5. Bar chart indicating dose response PK/PD of pMEK level
suppression with compound 12 at 10, 20, and 30 mg/kg in H292-
xenograft mice versus MCT vehicle (mean SEM is graphed). See
Supporting Information for further details.
stream target, pMEK S298). These results suggested that strong
polar interactions in this area were indeed crucial for driving
potency. One way to attenuate the pKa and lipophilicity of
D
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Letter
benefit. Other low pKa designs were also evaluated (compound
14 and the difluorinated compound 1519), but none of these
changes provided a compound with an improved profile relative
to 12.
basic amine extension on the compound was a likely cause of
these unfavorable attributes. To improve on these limitations, we
designed the 5-amino-1,3-dioxanyl group that helped to lower
the pKa and cLogP and ultimately derived 12. This optimized
compound demonstrated in vivo PK/PD effects consistent with
the observed potency and pharmacokinetic properties. We are
currently utilizing this molecule to further study PAK1 function
in cancer and other disease contexts.
Next, the X-ray crystal structure of 12 in PAK1 was determined
(Figure 2). The structure confirmed that the binding mode of 12
was indeed as expected. The methylpyridine “head-group” binds
in the pocket bordered by the αC-helix (with Glu315 stacking
interaction), catalytic Lys299, and gatekeeper Met344. The rest
of the core scaffold adopts an orientation similar to FRAX1036
(PDB: 5DFP) with two H-bond interactions at the hinge. The
newly introduced 5-amino-1,3-dioxanyl motif makes a bifurcated
H-bond interaction with backbone carbonyl of Asp393 and a
water molecule, which in turn makes a hydrogen bond with the
side chain of Asn394. Interestingly, the two annular oxygen
atoms are not making any observable interactions within the
binding pocket.
Having identified compound 12, we proceeded to further
characterize its selectivity and in vitro safety profile (Figure 3).
First, the kinase selectivity of 12 was determined against a panel
of 235 kinases (screened at 0.1 μM concentration equal to 58-
fold above PAK1 Ki). Compound 12 showed excellent kinase
selectivity and inhibited only eight out of the 235 kinases tested
other than PAK1 with inhibition >70%: PAK2, PAK3, KHS1,
Lck, MST3, MST4, SIK2, and YSK1. The IC50 of 12 against these
kinases was determined, and the values are shown in Figure 3A.17
In general, the compound demonstrated high selectivity for the
group I PAKs. In addition, a secondary pharmacology screen
against a panel of receptors, transporters, ion channels, and
enzymes20 showed remarkable lack of activity, only inhibiting the
serotonin receptors (5HT1A, 5HT1B, 5HT2A, 5HT2B, and
5HT4E) and the Na+ channel >50% (Figure 3B). These results
are in contrast to the activity of FRAX1036 in the same screen,
which showed significant activity against a majority of the
receptors and channels tested (data not shown). Crucially, there
was negligible activity for 12 against the hERG channel with IC50
> 10 μM in a patch clamp assay.
To assess the in vivo pharmacokinetic behavior of 12, we
dosed female CD-1 mice with either 2 mg/kg intravenously (i.v.)
or 25 mg/kg orally (p.o.) and monitored compound blood
concentrations over 8 h (Figure 4). Low blood clearance (CLblood
= 24.2 mL/min/kg) and an acceptable half-life (t1/2 = 53 min)
were observed.17 Additionally, good oral exposure (AUC = 30
μM·h) and high oral bioavailability (F = 80%) were achieved.
Taken together, these data indicated that we could achieve
sufficiently sustained levels of 12 to study target modulation and
pathway suppression in vivo. Moreover, in PK studies conducted
in cynomolgus monkey, compound 12 showed low clearance
(CLp = 3.4 mL/min/kg) and high oral bioavailability (F =
72%).17 These results suggest a potential for good human
exposure if the compound was advanced to the clinic.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00398.
Pharmacokinetic and pharmacodynamic study protocols,
protein production and crystallographic information, assay
protocols, compound synthesis, and characterization
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*(C.O.N.) Tel: 510-809-9290. E-mail: cndubaku@aduro.com.
*(J.J.C.) Tel: 650-467-8886. E-mail: crawfoj5@gene.com.
Present Addresses
⊥Aduro Biotech, 626 Bancroft Way, 3C, Berkeley, California
94710, United States.
#Blueprint Medicines, 215 First Street, Cambridge, Massachu-
setts 02142, United States.
○Biogen, 225 Binney Street, Cambridge Massachusetts 02142,
United States.
∇Janssen R&D, LMAD, 200 Great Valley Parkway, Malvern,
Pennsylvania 19355, United States.
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
Funding
Diffraction data were collected at beamline 08ID-1 at the
Canadian Light Source, which was supported by the NSERC, the
NRC, the Canadian Institutes of Health Research, the Province
of Saskatchewan, Western Economic Diversification Canada, and
the University of Saskatchewan at beamline 5.0.2 of the
Advanced Light Source. The Berkeley Center for Structural
Biology was supported in part by the NIH, the NIGMS, and the
Howard Hughes Medical Institute. The Advanced Light Source
was supported by the Director, Office of Basic Energy Sciences,
of the U.S. Department of Energy under Contract No. DE-
AC02−05CH11231.
To study target modulation in vivo, nude mice bearing H292
NSCLC xenografts were administered a range of three doses (10,
20, and 30 mg/kg) of 12.17 Tumors and blood were collected at 6
h postdose and analyzed for circulating drug levels and
alterations in the pharmacodynamic biomarker (pMEK S298).
Drug dose- and exposure-dependent reductions in pMEK were
consistent with the cellular potency and pharmacology of 12
(Figure 5).
In conclusion, in starting from an advanced PAK1 inhibitor,
FRAX1036, we were able to optimize the binding mode and
substituents, allowing us to ultimately balance potency,
permeability, and hERG activity. We postulated that the highly
Notes
The authors declare the following competing financial interest:
J.J.C., J.D., I.A., J.E., L.G., C.E.H., D.J., H.L., W.L., B.L., L.J.M.,
T.O., A.O., S.R., W.W., X.Z., Y.Z., E.B., and J.R. are employees
and stockholders of Roche.
ACKNOWLEDGMENTS
■
We thank A. Guillen, B. Murphy, M. Wong, Y. Liu, and D. Wang
(Genentech) for compound purification and analytical support.
We also thank D. Favor (Shanghai ChemPartner) for helpful
discussions.
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(15) Houben-Weyl: Science of Synthesis, 26.1.6.6.1, Hydrolysis of
O,O-Acetals, p 333.
ABBREVIATIONS
■
Cdc42, cell division control protein 42 homologue; HLM,
human liver microsomes; LLE, ligand lipophilic efficiency; MCT,
methylcellulose/Tween; PAK, p21-activated kinase; Papp
apparent permeability; pMEK, phosphorylated mitogen-acti-
vated protein kinase kinase; SEM, standard error of the mean
(16) Bi, L.; Zhao, M.; Gu, K.; Wang, C.; Ju, J.; Peng, S. Toward the
Development of Chemoprevention agents (III): Synthesis and Anti-
Inflammatory Activities of a New Class of 5-Glycylamino-2-substituted-
phenyl-1,3-dioxacycloalkanes. Bioorg. Med. Chem. 2008, 16, 1764−1774.
(17) See Supporting Information for more details.
,
(18) Inhibition curve was determined showing hERG IC50 > 10 μM in
ChanTest patch clamp assay.
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