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1. Introduction
2. Molecular biology and
oncogenic functions of PIM1
3. PIM1 expression in human
cancer diseases
4. Small molecule inhibitors of
PIM1 kinase
5. Expert opinion
Review
PIM1 kinase as a target for cancer
therapy
Anna Lena Merkel, Eric Meggers & Matthias Ocker†
Philipps University Marburg, Institute for Surgical Research, Marburg, Germany
Introduction: Inhibition of protein kinases has become a standard of modern
clinical oncology. PIM1 belongs to a novel class of serine/threonine kinases
with distinct molecular and biochemical features regulating various onco-
genic pathways, for example hypoxia response, cell cycle progression and
apoptosis resistance. PIM1 is overexpressed in human cancer diseases and
has been associated with metastasis and overall treatment response; in
experimental models, inhibition of PIM1 suppressed cell proliferation and
migration, induced apoptotic cell death and synergized with other
chemotherapeutic agents.
Areas covered: A PubMed literature search was performed to review the cur-
rently available data on PIM1 expression, regulation and targets; its implica-
tion in different types of cancer and its impact on prognosis are described.
We present ATP-competitive PIM1 inhibitors and the state of the art of
PIM1 inhibitor design. Finally, we highlight the development of the unusual
class of highly selective and potent organometallic PIM1 inhibitors.
Expert opinion: As PIM1 possesses oncogenic functions and is overexpressed
in various kinds of cancer diseases, its inhibition provides a new option in
cancer therapy. Based on the ability of highly selective organometallic
PIM1 inhibitors, promising in vivo applicability is expected.
Keywords: cancer, inhibitors, metal complexes, PIM1, serine/threonine kinase
Expert Opin. Investig. Drugs [Early Online]
1. Introduction
Malignant tumors continue to represent a global medical burden with more than
12 million new cases estimated per year and more than 7 million cancer-
related deaths overall [1]. In Western countries, while cardiovascular diseases show
a strong decline as a cause of death, cancer death rates remained stable over the
past decades and represent the most common cause of death at the age of
40 -- 79 [2]. The increasing identification and understanding of molecular pathways
altered in cancer diseases has recently paved the way for the development of more
specific anticancer agents, also known as targeted therapies [3,4]. Especially, inhibi-
tors of growth factors and their receptor signaling have been investigated intensively
and led to the approval of monoclonal antibodies (e.g., bevacizumab, cetuximab or
panitumumab) or small molecule kinase inhibitors (e.g., erlotinib, sunitinib or sor-
afenib) [5]. This latter class of compounds can effectively target intracellular tyrosine
kinases [6]. Yet, the specificity of these molecules is typically quite low due to the
high homology of tyrosine kinase families [7] and the redundancy of these pathways
allows cancer cells to either bypass the inhibited kinase or to develop resistance
against a specific inhibitor. Recently, the serine/threonine kinase family has entered
the focus of research. Small molecule inhibitors have been developed and
tested in clinical trials for some members of this family, for example, the
mTOR (mammalian target of rapamycin) complexes [8-10], polo-like kinases [11,12]
or aurora kinases [13-15]. However, the overall efficacy of these inhibitors still
10.1517/13543784.2012.668527 © 2012 Informa UK, Ltd. ISSN 1354-3784 1
All rights reserved: reproduction in whole or in part not permitted
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remains unsatisfying, with only low response rates and rather
marginal improvements concerning overall survival in clinical
trials [16-20].
Besides these well-established serine/threonine kinases,
members of the PIM kinase family have recently been
described to possess oncogenic and survival promoting prop-
erties [21,22]. We will here review the biological functions
and medical implications of PIM1 kinase expression in cancer
cells and highlight novel means of therapeutic intervention of
PIM1 activity including organometallic complexes to specifi-
cally inhibit PIM1 activity.
2. Molecular biology and oncogenic functions
of PIM1
2.1 Expression of PIM1 and its regulation
In 1984, PIM1 was identified as a common integration site
for murine leukemia virus [23]; subsequently, its serine/
threonine kinase activity was described [24]. PIM1 is expressed
in two isoforms: a 34 kDa short variant and a 44 kDa long
form; these two isoforms are synthesized by alternative trans-
lation initiation (Figure 1) [25]. As it is a stress--response kinase,
its expression can be induced by various cytokines, mitogens
and hormones such as GM-CSF, G-CSF, IL-2, IL-3, IL-5,
IL-7, IL-9, IL-12, IL-15, erythropoietin, Con A, PMA, inter-
feron g , steel cell factor and prolactin [26]. The most important
pathways in the activation of PIM1 expression are Jak-
STAT [27] and NF-kB [28]. Another transcription factor that
can induce the expression of PIM1 is ERG, which plays a
role in the initial stages of prostate carcinogenesis [29]. In solid
tumors, the expression of PIM1 in response to hypoxia plays a
crucial role and is HIF-1a dependent [28]. Furthermore,
PIM1 is a target of different miRNAs, such as miR1 [30],
miR33a [31] and miR328 [32], which reduce the translation
of PIM1-mRNA or induce its degradation.
In contrast to other kinases, PIM1 is constitutively
active [33]. Its activity is regulated at the level of expression
and stability. In normal peripheral blood lymphocytes, the
half-life of PIM1 is about 5 min, while it is prolonged in
the chronic myelogenous leukemia cell line K562
(20 min) [34]. PIM1 is able to autophosphorylate [35], although
the functional consequences of this phosphorylation still need
to be investigated. One study reports that PIM1 can also be
phosphorylated at Tyr218 by ETK, which enhances
PIM1 activity [36]. PIM1 is degraded via the ubiquitin-
proteasome pathway and can be protected from proteasomal
degradation by the binding of heat shock protein
Hsp90 [37]. In contrast, Hsp70 binds only to ubiquitinated
PIM1 and promotes its degradation [37]. Additionally, the
binding of the phosphatase PP2A mediates PIM1 dephos-
phorylation, ubiquitylation and proteasomal degradation
and is therefore a negative regulator [38].
2.2 Targets and functions of PIM1
Several proteins and pathways with oncogenic properties, for
example cell cycle regulation and apoptosis control, have
been identified as targets of PIM1 kinase activity.
PIM1 has been shown to stimulate cell cycle progression at
various stages (Figure 2A). While phosphorylation of Cdc25A
leads to enhanced G1/S transition [39], phosphorylation of
Cdc25C induces increased G2/M transition [40]. A different
way of how PIM1 regulates Cdc25C activity is the phosphor-
ylation of C-TAK1, which induces its nuclear export and ena-
bles Cdc25C to be active [41]. Another cell-cycle-related target
of PIM1 is the CDK inhibitor p21cip1/waf1. Here, phosphory-
lation at Thr145 leads to the nuclear export and inactivation
of p21cip1/waf1 [42]. The phosphorylation of the CDK inhibitor
p27Kip1 at Thr157 and Thr198 induces its proteasomal degra-
dation and cell cycle progression. Additionally, the transcrip-
tion of p27Kip1 is reduced due to the phosphorylation and
inactivation of the transcription factors FoxO1a and
FoxO3a [43]. Another mechanism of p27Kip1 regulation is
the phosphorylation of its ubiquitin ligase Skp2 at
Thr417 by PIM1 which leads to Skp2 stabilization and
p27Kip1 degradation [44,45]. Moreover, PIM1 plays a role in
promoting mitosis as it interacts with NuMA, dynein/
dynactin and HP1b. Here, PIM1 bridges the kinetochores
via HP1b to the spindle assembly complex [46].
In additionto controlling cell growth pathways, PIM1 is
able to block apoptotic cell death and thus can act as an onco-
genic survival factor (Figure 2B). Phosphorylation of the
pro-apoptotic protein Bad at Ser112 leads to proteasomal
degradation and shifts the apoptosis threshold towards sur-
vival [47]. The inactivation of ASK1 through phosphorylation
at Ser83 leads to decreased kinase activity and subsequently
less phosphorylation of the stress kinases JNK and p38, which
is associated with less caspase 3 activation and reduced cell
death [48]. Apoptosis can also be blocked by PIM1 via the
phosphorylation of PRAS40 at Thr246, which leads to the
dissociation of PRAS40 from the mTOR complex and
increases mTOR kinase activity and with increased phosphor-
ylation of the mTOR downstream targets 4EBP1 and
p70S6Kinase [49]. Interestingly, activation of mTOR has
Article highlights.
. The serine/threonine kinase PIM1 regulates numerous
oncogenic processes like hypoxia response, cell survival,
apoptosis and migration in cancer cells.
. PIM1 is commonly overexpressed in human cancers and
represents an interesting novel therapeutic target.
. Inhibition of PIM1 inhibits cancer cell growth and
migration synergistically with other
chemotherapeutic agents.
. Highly potent and selective organic and organometallic
PIM1 inhibitors are available which all target the ATP
binding site in an ATP competitive fashion.
. Binding of PIM1 inhibitors can be grouped into two
classes: ATP-mimics and non-hinge binders.
This box summarizes key points contained in the article.
A. L. Merkel et al.
2 Expert Opin. Investig. Drugs [Early Online]
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been shown to interfere also with autophagy pathways, which
indicate additional roles of PIM1 in energy metabolism and
stress response [50,51].
Moreover, PIM1 influences the activity of different tran-
scriptional regulators, for example NFATc1, p100, RUNX,
SOCS1, RelA/p65, c-Myb and c-Myc (reviewed in [52]). The
phosphorylation of c-Myc at Ser62 and Ser329 increases pro-
tein stability and thereby the transcriptional activity. c-Myc
recruits PIM1 to the E boxes of its target genes, in which
PIM1-dependent phosphorylation of histone H3 on Ser10
(H3S10) contributes to the activation of target genes and cellu-
lar transformation [53]. Elevated PIM1 levels seem to induce the
p53 pathway in different cancer cell lines and murine embry-
onic fibroblasts. Here, PIM1 associates with and phosphory-
lates Mdm2 at Ser166 and Ser186 leading to stabilization
of Mdm2 and p53. PIM1 also induces endogenous ARF,
p53, Mdm2 and p21cip1/waf1 in primary murine embryonic
fibroblasts and stimulates oncogene-induced senescence [54]. It
has also been described that the overexpression of PIM1 can
inhibit cell and tumor growth by inducing senescence and
DNA damage in a p53-dependent manner in human prostate
cancer cells [55]. Moreover, PIM1 can mediate chemoresistance
through the phosphorylation of the efflux transporter and puta-
tive stem cell marker BCRP/ABCG2 at Thr362 and the knock-
down of PIM1 resensitized prostate cancer cells to
chemotherapeutic drugs [56]. Additionally, PIM1 plays a role
in hypoxia-induced chemoresistance [57] and tumor forma-
tion [51]. In line with this, PIM1 has also been shown to be
involved in regulating homing processes of hematopoietic cells
by interacting with the CXCR4-CXCL12 system [58], which is
also an important regulator of solid tumor metastasis formation
and thus indicates an additional oncogenic function for PIM1,
which needs to be elucidated further.
3. PIM1 expression in human cancer diseases
Besides its association with murine leukemia [59,60],
alterations in PIM1 signaling have been found in various
HIF-1α
Hypoxia Cytokines, mitogens, hormones
AKT/PKB
PIM1
PIM1
PIM1
ETKPIM1
PP2A
+p
+p
PIM1 p
p
Hsp90
Proteasome
Hsp70
PIM1 S (34 kDa)
PIM1 L (44 kDa)
AAA
miR1
miR33a
miR328
Biological
functions
PI3K JAK
STAT
NF-κB
PIM1
Ubi
Ubi
Ubi
Ubi
Figure 1. Molecular regulation of PIM1 expression and functions. Various stimuli like hypoxia or growth factors activate
PIM1 expression via different signaling pathways. After transcription, PIM1 mRNA can be destabilized by different miRNAs or
be expressed as two isoforms of PIM1. PIM1 can exert its biological functions either alone or as a complex with Hsp90. PIM1 is
able to autophosphorylate and can be phosphorylated by ETK at a different position. Inactivation of PIM1 is mediated by
complex formation with Hsp70 or after dephosphorylation by PP2A, both of which lead to polyubiquitination and subsequent
degradation via the proteasome.
PIM1 kinase as a target for cancer therapy
Expert Opin. Investig. Drugs [Early Online] 3
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human tumor diseases too [52,61]. In hematologic malignan-
cies, PIM1 expression correlated with poor prognosis in var-
ious leukemias [62], mantle cell lymphoma [63] and diffuse
large B-cell lymphoma [64]. In solid tumors, overexpression
of PIM1 has been detected in bladder cancer (with higher
levels in invasive than in non-invasive cancers) [65] and in
prostate cancer specimens, where it was also correlated with
poor prognosis and therapy response [66-70]. Similar findings
were obtained for esophageal [71] and gastric cancer [72,73],
where PIM1 was upregulated after H. pylori infection in a
cell culture model [74] and in gastric epithelia from
patients [75]. In head and neck cancer, PIM1 was highly
p-Bad
Bcl2 JNK
Caspase 3 function
Induction of apoptosis
Increased
metabolism
p-4EBP1 p-p70S6K
p38 mTOR
p-ASK1
PIM1
p-PRAS40
T
ar
ge
t
m
ol
ec
ul
es
D
ow
ns
tr
ea
m
ef
fe
ct
s
p-c-Myc p-Cdc25A
p-Cdc25C
PIM1
G1/S-transition
G2/M-transition
Incresed
transcription
Degradation
Active
cyclin/Cdk
Cell cycle progression
Kinetochore
assembly
T
ar
ge
t
m
ol
ec
ul
es
D
ow
ns
tr
ea
m
ef
fe
ct
s
p-NuMA
p-HP1β
p-dynein/
p-dynactin
p-p21Cip1/Waf1
p-p27kip1
A.
B.
Figure 2. Oncogenic signaling pathways of PIM1. A. Cell cycle control by PIM1. Phosphorylation of target molecules leads to
progression of the cell cycle. PIM1-mediated phosphorylation of cell cycle inhibitors activates cyclin/Cdk complexes, stimulates
cell cycle checkpoint transitions and facilitates the kinetochore assembly as a prerequisite for mitotic division. Additionally,
the transcription of c-Myc target genes is activated. B. Inhibition of apoptosis by PIM1 is mediated via phosphorylation of
target molecules like Bad, ASK1 or PRAS40 which inhibit pro-apoptotic functions (e.g., the JNK/p38-caspase 3 axis) or
stimulate anti-apoptotic (Bcl2) and pro-survival (mTOR) pathways.
A. L. Merkel et al.
4 Expert Opin. Investig. Drugs [Early Online]
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expressed in more advanced stages and associated with poor
prognosis and lymph node metastasis [76,77]. Here,
PIM1 expression was also shown to be predictive for
response to radiation therapy [78]. Interestingly, PIM1 was
also found as a tumor-associated antigen in blood from colo-
rectal cancer patients and has been proposed as a sensitive
novel biomarker for this disease [79]. In contrast to these
findings, a significant downregulation of PIM1 mRNA was
found in primary non-small-cell lung cancer and PIM1 was
even further suppressed in lymph node metastases compared
with nodal negative tumors [80]. Elevated expression of
PIM1 has also been described for patients with pancreatic
cancer. Yet, high levels of PIM1 mRNA were associated
with a prolonged median survivalof 23.4 months compared
with 13.8 months in patients with low PIM1 mRNA [81].
This is surprising as PIM1 has been shown to be directly cor-
related to oncogenic K-ras mutations and hypoxia also in
pancreatic cancer models [51,82]. PIM1 was also reported to
contribute to radio- and chemotherapy resistance in pancre-
atic [83], prostate [84], head and neck [78] or lung cancer [85],
which confirms the above described oncogenic properties
in modulating hypoxia response or apoptosis signaling in
tumor cells [57].
The change in PIM1 expression cannot be explained by
gene rearrangements or amplification [62,86], although somatic
hypermutations have been described in different lympho-
mas [87,88]; also this cannot be the reason for increased
PIM1 expression.
4. Small molecule inhibitors of PIM1 kinase
All reported small-molecule PIM1 inhibitors are ATP-
competitive binders. Crystal structures of PIM1 reveal the
typical two-lobe protein kinase architecture connected by a
so-called hinge region, with the catalytic ATP-
binding domain positioned in a deep intervening cleft
(Figure 3) [33,35,89-92]. The N-terminal lobe is comprised pri-
marily of anti-parallel b-sheets and the C-terminal lobe
mainly of a-helices. Unique features of PIM1 are a
b-hairpin insert located at N-terminal to helix aC and,
most importantly, the presence of a proline residue at position
123 within the hinge region. Almost all protein kinases form
two canonical hydrogen bonds between the backbone of the
hinge region and the adenine nucleobase of ATP, whereas in
PIM kinases one hydrogen bond is prevented by this proline
residue, which is probably responsible for the relatively high
Km value for ATP. While no crystal structure has been
reported yet for PIM3, PIM1 and PIM2 adopt constitutively
active conformations in their crystal structures, regardless of
the phosphorylation state of the activation segment [93].
Several classes of PIM1 inhibitors have been described
which cover a significant number of different chemical core
structures, ranging from indolocarbazoles, bisindolylmalei-
mides, naphthyridines, pyridazines and isoxazoles to thiazoli-
dine-2,4-diones, thienopyrimidinones, pyridones and
isoxazoloquinolines (Figure 4) [90-92,94-108]. Staurosporine ana-
logs, inhibitors of casein kinases, PKC or phosphatidylinositol
3 kinase have a rather broad and unspecific profile on
PIM1 inhibition [52,109]. Recently, more specific imidazopyri-
dazine derivatives like ETP-45299 [110], K00135 [107] or
SGI-1776 [111,112] or the dihydropyrrolocarbazole derivative
DHPCC-9 [100,113] have been designed [114]. A monoclonal
anti-PIM1 antibody, which binds to cytosolic, nuclear and
membranous PIM1 and induces apoptosis in human and
murine cancer cells has been described in preclinical mod-
els [115]. So far, only SGI-1776 has been investigated in pre-
clinical toxicity screening [116] and in two early phase clinical
trials against refractory leukemia (NCT01239108), lym-
phoma or prostate cancer (NCT00848601). All mentioned
compounds have been shown to inhibit cell proliferation
and migration and to influence apoptosis by resensitizing
tumor cells to conventional chemotherapeutic agents
[110,112,117] or small-molecule kinase inhibitors [118] at low
micromolar concentrations.
While all reported compounds have an ATP-competitive
mode of action on inhibiting PIM1, one can classify them
into two distinct binding modes: close ATP mimics and
non-hinge binders. The unselective broad-spectrum protein
kinase inhibitor staurosporine and its maleimide analogs
such as bisindolylmaleimides or the class of organometallic
C-terminal lobe
A-loop
Hinge
N-terminal lobe
Arg122
Pro123
Glu121
P-loop
b-hairpin
insertaC
Figure 3. PIM1 structure in complex with the non-
hydrolyzable ATP analog AMPPNP (pdb code 1YXT). The
hydrogen bond between the adenine base and the back-
bone carbonyl group of Glu121 is highlighted.
PIM1 kinase as a target for cancer therapy
Expert Opin. Investig. Drugs [Early Online] 5
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pyridocarbazole complexes represent the first class and closely
mimic the binding of ATP to the hinge region. For
example, Figure 5 shows the binding of the highly potent orga-
noruthenium complex (S)-DW12 to the ATP binding site of
PIM1 (IC50 = 0.2 nM at 100 µM ATP) [92]. The pyridocarba-
zole heterocycle mimics the hydrogen-bonding pattern of the
adenine base of ATP by establishing one hydrogen bond
between the NH group of the maleimide moiety and the
backbone carbonyl group of Glu121, whereas crystal
structures of this class of organometallic complexes to other
protein kinases typically reveal a second hydrogen bond to
one of the carbonyl groups of the maleimide; this is prevented
in PIM1 by the proline residue at position 123 [119]. Addi-
tional water-mediated hydrogen bonds are formed between
the hydroxyl group at the indole of (S)-DW12 and Lys67,
Glu89 and Asp186. The organometallic inhibitor is tightly
bound in the ATP binding site through a large number of
hydrophobic contacts. Maybe most interestingly, although
Staurosporine
IC50 = 10 nM
Pyridone
IC50 = 50 nM
Isoxazolo[3,4-b]quinolinedione
Ki = 2.5 nM
Bisindolylmaleimide
IC50 = 10 nM
[1,2,4]triazolo[4,3-b]pyridazin
Ki = 11 nM
Benzo[4,5]thieno[3,2-d]pyrimidinone
Ki = 5 nM
Benzo[c]isoxazole
Ki = 91 nM
Thiazolidine-2,4-dione
IC50 = 13 nM
Benzo[c][2,6]naphthyridine
IC50 = 5 nM
Imidazo[1,2-b]pyridazin (K00135)
IC50 = 120 nM
(S)-DW12
IC50 = 0.2 nMATP
Pro123
Arg122
N
O
N
H
R
N
O
O
H
N
H
N
N
N
N
O
HO
HO
OPPP
Glu121
H
NN
H
N
O
O
H
O
HN
N
H
N
O
Ru
O
C
O
OH
N
NN
H
N
O O
S
NH
H2N
N
N
HN
CI
NH
N
N
N
N
N
O
N
H N
N
N
N
N
H
CF3
N
O
N
N NH2
CI
S
NH
O
O
F
S
N
NH
Br
O
NMe2
HO HN
O
CN
Br
HO
CI
O O
N
H
O
N
Figure 4. Selection of ATP-competitive PIM1 inhibitors. The reported IC50 or Ki values are shown.
A. L. Merkel et al.
6 Expert Opin. Investig. Drugs [Early Online]
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this organometallic scaffold is a conventional ATP competi-
tive binder, the unique shape of the complex permits novel
interactions with the glycine-rich loop as illustrated
in Figure 5. The residues Leu44, Gly45, Phe49 and
Val52 together form a small hydrophobic pocket that
appears perfectly suited for the CO ligand. In contrast to
organic carbonyl functional groups, metal coordinated CO
lacks any significant dipole moment and therefore behaves
like a very hydrophobic ligand. It is worth noting that in
this and related crystal structures the metal is not involved
in any direct interaction and merely serves as a structural
center. Therefore, it is not surprising that replacing ruthe-
nium in (S)-DW12 against osmium leads to a compound
with identical inhibition properties [120]. Metallo-pyridocar-
bazole complexes currently represent the class of compounds
with the highest affinity for PIM1 with IC50 values reaching
down to 0.075 nM and demonstrating exquisite PIM1
selectivities [121,122].
The second class of ATP competitive inhibitors is distin-
guished by the absence of any canonical hydrogen bonds
with the hinge region. For example, Figure 6 displays the bind-
ing of a benzo[c]isoxazole derivative to the active site of
PIM1 [96]. No classical hydrogen bond is observed with the
hinge region but a pyrimidine moiety forms a hydrogen
bond with Lys67 which is located at the opposite site of the
pocket (Figure 6A). However, the authors discuss an unusual
weak hydrogen bond between an aromatic CH and the back-
bone carbonyl group of Glu121. The binding of the imidazo
[1,2-b]pyridazine inhibitor K00135, a compound that served
as a lead structure for the development ofSGI-1776, is shown
in Figure 6B and also exploits a hydrogen bond with
Lys67 [107]. K00135 was demonstrated to be surprisingly
selective for PIM1 over more than 50 diverse serine/
threonine kinase catalytic domains and the authors speculated
that this is due to the combination out of the unusual
PIM1 active site architecture, together with the unconven-
tional binding mode. Interestingly, PIM2 was inhibited sig-
nificantly weaker by a factor of around 100-fold although
the amino acid residues of PIM1 and PIM2 are almost iden-
tical so that this might be the result of a dynamic effect. Over-
all, it appears to be a trend of many PIM inhibitors that
selectivity for PIM1 and PIM3 is observed over PIM2. This
selectivity might be the result of differences in the dynamic
properties of the individual PIM isoforms [52].
5. Expert opinion
Effective and well-tolerable agents are still an unmet medical
need in today’s cancer therapy. Despite the introduction of
so-called targeted therapies, the overall survival of cancer
patients is still disappointing. Commonly, these targeted
therapies use tyrosine kinase inhibitors that show a high level
Asp186
Val52
Phe49
Gly45
Leu44
H2O
H2O
C.
B.A.
Glu89
Glu121
Arg122
Pro123
Lys67
Figure 5. Structure of organoruthenium half-sandwich complex (S)-DW12 bound to the ATP-binding site of PIM1 in an ATP-
mimetic fashion (pdb code 2BZI). A. Overall cartoon representation including van der Waals surface. B. Hydrogen bonding
interactions of (S)-DW12 with the hinge region and water-mediated interactions to Glu89 and Asp186. C. Interactions with
the glycine-rich loop.
PIM1 kinase as a target for cancer therapy
Expert Opin. Investig. Drugs [Early Online] 7
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of side effects and rapidly lead into resistance as tyrosine
kinase pathways are highly redundant in tumor cells.
PIM1 represents a constitutively active serine/threonine
kinase which is distinct from other classes of kinases by both
its molecular structure and its molecular regulation.
PIM1 controls oncogenic signaling pathways like hypoxia,
cell cycle control or apoptosis resistance and has been shown
to be overexpressed in various human cancers and to be
associated with metastasis and overall prognosis. Therefore,
PIM1 is an interesting novel target for targeted drug therapy.
PIM1 inhibition by small molecules has been accomplished
with a variety of chemical scaffolds through the development
of ATP competitive binders, either by mimicking closely the
hinge-binding of ATP or by exploiting other areas of the
active site. Selected compounds have demonstrated efficacy
in preclinical models and are currently undergoing early-
phase clinical trials. However, the class of organometallic
PIM1 inhibitors displays a significantly higher specificity
and binding affinity down to picomolar Ki values compared
to purely organic inhibitors. This can be traced back to a
perfect shape complementarity provided by the structural
metal center combined with the ability to undergo unique
interactions with the flexible glycine-rich loop of PIM1.
It is, of course, still necessary to better characterize the
effect of these organometallic inhibitors on the molecular level
in vitro. Here, the numerous interactions and signaling path-
ways influenced by PIM1 open further possibilities for combi-
nation approaches with tyrosine kinase inhibitors or direct
pro-apoptotic stimulators to further increase the cytotoxic
effects at probably even lower concentrations. Yet, the high
number of available compounds demands further pharmaco-
kinetic and pharmacodynamic studies in animal models that
are at present still missing for most of these highly potent
inhibitors. Based on their chemical properties, excellent
in vivo applicability is expected and we therefore believe that
clinical trials in human patients can be conducted in the
near future.
Acknowledgements
We apologize to all colleagues whose work could not be cited
due to space limitations.
Declaration of interest
The authors state no conflict of interest and have received no
payment in preparation of this manuscript.
Lys67
Lys67
Hinge
Hinge
A.
B.
Figure 6. Structures of non-hinge binding inhibitors bound
to the ATP-binding site of PIM1. A. A benzo[c]isoxazole (pdb
code 3BGP). B. Imidazo[1,2-b]pyridazine K00135 (pdb code
2C3I). Highlighted are the hydrogen bonds to Lys67.
A. L. Merkel et al.
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Affiliation
Anna Lena Merkel1, Eric Meggers2 &
Matthias Ocker†1
†Author for correspondence
1Philipps University Marburg, Institute for
Surgical Research, Baldingerstrasse, Marburg,
35033, Germany
E-mail: Matthias.Ocker@staff.uni-marburg.de
2Department of Chemistry, Philipps University
Marburg, Institute for Surgical Research,
Baldingerstrasse, Marburg, 35033, Germany
A. L. Merkel et al.
12 Expert Opin. Investig. Drugs [Early Online]
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