Human Molecular Genetics 2005 14(Review Issue 2):R291-R300; doi:10.1093/hmg/ddi269
© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Small molecule intervention in microtubule-associated human disease
Jantje M. Gerdes1 and
Nicholas Katsanis1,2,*
1McKusick-Nathans Institute of Genetic Medicine and
2Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD 21205, USA
* To whom correspondence should be addressed at: McKusick-Nathans Institute of Genetic Medicine, 533 Broadway Research Building, 733 N. Broadway, Baltimore, MD 21205, USA. Tel: +1 4105026660; Fax: +1 4105020697; Email: katsanis{at}jhmi.edu
Received June 30, 2005; Accepted July 20, 2005
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ABSTRACT
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Microtubules are essential for a number of cellular processes
that include the transport of intracellular cargo or organelles
across long distances and the assembly of the mitotic spindle.
The identification of numerous microtubule-associated proteins
and the progressive elucidation of the mechanisms of microtubule
assembly and transport are beginning to have a profound impact
on the study and treatment of human genetic disease. A number
of seemingly unrelated phenotypes have now been linked to microtubular
dysfunction, especially in systems dependent heavily on microtubule-based
transport, such as neurons and ciliated cells. In parallel,
the association of microtubule transport defects with human
genetic disease has led to the realization that targeting various
aspects of microtubular biology with small molecules might offer
new therapeutic paradigms, including the development of new
therapeutic utility for seemingly old drugs. In this review,
we discuss the use of small molecules in the investigation of
microtubule-associated processes and particularly the screens
of chemical compound libraries for the identification of lead
compounds with potential utility in microtubule-associated disease
processes.
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MICROTUBULAR TRANSPORT
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Microtubules play a central role in cellular transport, structural
integrity and cellular architecture (Fig.
1). As such,
it is not surprising that perturbations of microtubule dynamics
and transport can lead to a broad range of human phenotypes.
These defects are particularly prominent in structures and processes
dependent heavily on the microtubule network, such as the central
nervous system, where proper neuronal function is dependent
on transport of cargo across long distances (up to 1 m
in humans) and the microtubule-rich cilium of many eukaryotic
cell types (1
–5
).
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Figure 1. Schematic presentation of the role of microtubules in various cellular processes. The microtubules (blue) protrude from the microtubule-organizing center (MTOC) which is located in proximity to the nucleus towards the cell periphery. Examples of small molecule effectors interfering with these microtubular processes are shown in red.
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Mammalian cells regulate their architecture and active transport
requirements by utilizing three major types of filaments: microtubules,
microfilaments and intermediate filaments. Intermediate filaments
and microfilaments fulfill primarily structural and mechanical
functions, whereas microtubules are critical for the intracellular
transport of cargo, as well as the assembly of the mitotic spindle.
Like microfilaments, microtubules are polarized structures and
assemble from heterodimers of
- and ß- tubulin in
a GTP-dependent fashion. Microtubule dynamics play an important
role in mitosis and the cell cycle (6
), and interference with
these dynamic processes can trigger apoptosis (7
). Transport
along the microtubule network is accomplished by microtubular
dynamics or by microtubule-associated motor proteins and other
microtubule-associated proteins (MAPs), which either actively
move cargo along the microtubules (motor proteins) or can serve
as docking molecules to bind cargo to motor proteins (8
).
Microtubule-associated motor proteins are divided into two major protein families, kinesins and dyneins, both of which consist of globular motor domains that typically share high sequence homology among the particular protein family; it is the adjoining rod-like structure that is more diverse (2,9,10). Members of the dynein family generally enable transport of cargo from the cell periphery to the center (9,11), whereas the much larger kinesin superfamily is involved primarily with transport towards the cell periphery, with the exception of C-terminal kinesins which, though similar in structure, facilitate transport towards the cell center (9,12).
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MICROTUBULE-BINDING SMALL MOLECULES
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Microtubules pose an interesting, albeit challenging, target
for specific remedial intervention. To date, all drugs or small
molecules known to interact with microtubules disrupt microtubule
dynamics by either stabilizing or destabilizing the polymerized
state. Disrupting microtubule dynamics affects mainly rapidly
dividing cells, such as cancer cells, which is why these small
molecules have been considered potent agents for chemotherapy
(Fig.
1) (6
). Docetaxel (or taxotere) (
1) is a derivative
of the natural product Paclitaxel (Taxol®) (
2), a known
stabilizer of tubulin interaction. In contrast, Podophyllotoxin
(
3), etoposide (
4), vinblastine (
5), vincristine (
6) and vinorelbine
(
7) are anticancer drugs that inhibit or disrupt microtubules
and microtubule assembly. In addition, the antifungal and antimitotic
FDA approved drug griseofulvin (
8) inhibits mitosis in metaphase
and interacts with polymerized microtubules and MAPs. Currently,
there are 16 microtubule interacting compounds listed in the
chemical reference database ChemBank, an electronic repository
of structural information and bioactivity data of chemical compounds
(
http://chembank.broad.harvard.edu) (Table
1). In addition
to the aforementioned known drugs, there are more destabilizers
listed including the natural products cytochalasin A (
9) and
E (
10), TN-16 (
11), myoseverin (
12), nocodazole (
13), vindesine
(
14), the depsipetide Phomopsin A (
15) and d-24851 (
16). As
microtubule dynamics are of vital importance for all dividing
cells, disruption of this process will affect both cancerous
and normal cells alike; the increased rate of proliferation
of cancer cells renders antimotic drugs
1–8 useful and
potent inhibitors of cancer growth, but also explains the drastic
side effects of cancer chemotherapy such as hair loss and a
decrease in red blood cells, because the proliferation of normal
tissue is also inhibited.
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SPECIFIC INHIBITORS OF MAPS
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Monastrol (
17) was identified when screening for abnormal mitotic
behavior in cells treated with a library of small molecules
(Fig.
2) (13
). Treatment with monastrol results in replacement
of the bipolar mitotic spindle with a monastrol microtubule
array surrounded by a ring of chromosomes, which in turn causes
the cells to enter mitotic arrest. Subsequently, the human kinesin-like
protein Eg5 was identified as the target of monastrol (
17) (13
).
In spite of considerable sequence homology shared by all kinesin
proteins, no effect on conventional kinesin-associated microtubule
motility was observed. Similarly, there was no detectable alteration
in the localization and organization of the Golgi apparatus
or lysozymes. Therefore, monastrol is not considered a general
inhibitor of motor proteins but an example of a selective inhibitor
of Eg5, thereby representing the first selective inhibitor of
a microtubule-associated motor protein. Until then, the non-hydrolyzable
ATP analog AMP-PNP (
18) and the marine natural product adociasulfate-2
(
19) (14
) were the only kinesin inhibitors known, both suffering
drawbacks because of their poor cell permeability and selectivity.
Subsequent to the discovery of monastrol, the target of terpendole
E (
20), a natural product with known antimitotic properties,
was also identified as kinesin Eg5 (15
). Although the binding
site for terpendole E (
20) is not known, the mechanism of action
of adociasulfate-2 was established to be the area of the microtubule-binding
site of the kinesin heavy chains (14
). The mechanism of action
for monastrol has been shown to be non-competitive with respect
to ATP or microtubule binding (16
). However, monastrol has been
shown to bind to the motor domain of Eg5 (16
,17
) and is thus
an allosteric inhibitor of Eg5 activity. Currently, several
Eg5 inhibitors are undergoing clinical evaluation (18
,19
).
In stable microtubules, there is an abundance of acetylated
-tubulin, which is absent from more dynamic cellular structures
such as neuronal growth cones or the leading edges of fibroblasts.
The role of
-tubulin acetylation remains unclear and only recently
an enzyme responsible for deacetylation has been identified:
histone deacetylase 6 (HDAC6) (20
). Unlike other histone deacetylases,
HDAC6 is localized exclusively in the cytoplasm, in particular
to punctate structures concentrated perinuclearly, as well as
the leading edge of the cell (20
). In this regard, it is reminiscent
of p150
Glued, with which it colocalizes. HDAC6 shows deacetylase
activity with respect to polymerized microtubules; free
/ß-tubulin
dimers are not deacetylated. In a cell motility assay, NIH 3T3
cells overexpressing wild-type HDAC6 move at least 3.5-fold
faster than control cells in response to serum. This apparent
role in the regulation of cell motility by controlling microtubule
acetylation at the leading edge makes HDC6 an attractive target
in drug development for its implications in metastasis and angiogenesis.
Currently, four histone deacetylase inhibitors are undergoing
clinical trials for cancer treatment, mainly in combination
therapy (21
). Although most histone deacetylase inhibitors also
affect microtubule acetylation, there were no selective inhibitors
for microtubule acetylation. In a multidimensional, chemical
genetic screen of over 7300 small molecules, tubacin (
21) a
selective and reversible inhibitor of HDAC6 related
-tubulin
acetylation in mammalian cells was discovered (22
). Targeting
of tubulin acetylation does not affect cell cycle progression.
Further investigation revealed that deacetylation does not seem
necessary for microtubule depolymerization. In neurodegenerative
disorders, hypoacetylation is frequently observed; increasing
the levels of acetylated
-tubulin by the inhibition of HDAC6
might therefore not only be implicated in antimetastatic and
antiangiogenic therapy but also in that of neurodegenerative
disorders.
Many neurodegenerative diseases are characterized by inclusion bodies like Lewy bodies or aggresomes (23,24). The hypothesis that aggresome formation is part of a cytoprotective response remains an issue of debate. A recent study demonstrated the role of HDAC6 in the formation of aggresomes (25). A ubiquitin-binding zinc finger domain in HDAC6, as well as its affinity for dynein, suggest that HDAC6 might represent a link between polyubiquitinated misfolded proteins and dynein, thereby enabling the transport along the microtubules towards the MTOC where aggresomes develop. Aggresomes of misfolded proteins have a similar appearance to Lewy bodies and accumulate upon the inhibition of proteasome activity in cells. It has been shown that both aggresomes and Lewy bodies contain HDAC6. As cells are more sensitive to polyubiquitinated misfolded protein stress without the presence of functional HDAC6 and hence in the absence of aggresome formation, it is likely that aggresome formation is part of a cytoprotective response.
A study designed to investigate the role and mechanism of aggresome formation in mammalian cells employed a high throughput assay to screen for small molecules that disrupt aggresome formation in cultured cells (26). Among general microtubule inhibitors and protein synthesis inhibitors, the assay identified 12 candidate-specific aggresome inhibitors. These can be sorted into two groups, one being cardiac glycosides and the other comprising two compounds: Scriptaid (22), a previously known histone deacetylase inhibitor, and DPD (23), a flavinoid which up to that point did not have any associated biological activity (26). Upon treatment with either compound, the misfolded protein forms small granular structures throughout the cytoplasm, but assembly into aggresomes is almost completely suppressed. Other HDAC inhibitors show the same effect, and neither Scriptaid nor DPD have a significant effect on MTOC formation or Golgi localization and assembly (26). A portion of the dynactin complex precipitates with the misfolded proteins, suggesting that it may bind to misfolded proteins themselves or their ubiquitin labels. Interestingly, DPD does not inhibit deacetylase activity, which might imply that the two inhibitors have a different mechanism of action or that deacetylase activity alone is not sufficient for aggresome formation.
A recent study hypothesized that the inhibition of both proteasomal and aggresomal proteins degradation induces the accumulation of polyubiquitinated proteins and significant cell stress, thus triggering apoptosis (27). A combination of bortezomib (a proteasome inhibitor) and tubacin (21) yielded enhanced cytotoxicity even in plasma cells isolated from the bone marrow of multiple myeloma patients. The cellular stress response is mediated by both c-Jun N-terminal kinase and caspase/PARP cleavage (27). Therefore, the combination therapy of certain cancer types using proteasome and aggresome inhibitors seems promising for clinical evaluation.
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SMALL MOLECULE INTERVENTION IN NEURODEGENERATIVE DISEASE
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Huntington disease (HD) is a progressive neurodegenerative disorder
characterized by uncontrolled movements, changes in personality
and progressive dementia; patients die within 10–20 years
of onset. HD, as well as a number of other neurodegenerative
disorders, have been linked to polyglutamine expansion (28
);
in the case of HD, the causative gene
Htt has been shown to
be expanded within the open reading frame. At the cellular level,
one major hallmark is the formation of aggregates that contain
polyQ-Htt protein in or near the nuclei of affected neurons,
both in brain tissue of patients and HD transgenic mice (29
–31
).
Histological analyses have shown significantly dysfunctional
neurons, as well as loss of neurons, especially the medium spiny
neurons of the striatum (32
). Motor and cognitive defects have
been observed in both patients and murine models of HD before
any neurodegeneration is detected (33
). Yeast-2 hybrid screening
and glutathione
S-transferase-pulldown experiments showed that
wild-type Htt binds both HAP1 and the p150
Glued subunit of dynactin
and seems to play a role in microtubule-dependent axonal transport
(34
,35
). Although the role of inclusion body or aggresome remains
unclear, therapeutic strategies that aim to avoid polyQ-aggregation
have shown some efficacy
in vivo (36
,37
). A study aimed at identifying
potential inhibitors of polyQ-dependent aggregation in HD neurons
used initially a yeast model of HD aggregation to screen 16 000
compounds (Fig.
2) (38
). The yeast strain was modified
to express a GFP labeled Htt homolog with an extended polyQ-trait
which formed aggregates and proved to be cytotoxic (39
). Overall,
the modified yeast strain showed reduced growth compared with
wild-type yeast. The initial round of selection tested for compounds
that caused at least a 25% increase in OD
600 and/or EGFP fluorescence
compared with controls (38
). Following rounds of screening included
a visual assessment of aggresome formation in treated mammalian
neuronal cells (PC12) and filter trap assays for aggresome formation
in the presence of candidate compounds (both
in vitro and
in vivo). Final
in vivo assessments of the candidate compounds
included the polyQ-aggregation in hippocampal slices derived
from HD transgenic mice and in a
Drosophila HD model (38
). Of
nine compounds able to rescue growth in the yeast model, four
did not block aggregation directly, suggesting that they are
probably not targeting soluble or aggregated polyQ-Htt directly.
Compound
24 inhibited aggresome formation both
in vitro and
in vivo and showed amelioration of neurodegeneration in a dose-dependent
manner in the HD
Drosophila model (38
), thereby representing
a strong lead structure for human drug development. Moreover,
the combination of initial cell-based high-throughput screening
and subsequent evaluation in a diverse set of
in vitro and
in vivo secondary assays that included animal models (brain slices
of HD transgenic mice and a HD
Drosophila model) should allow
for screening of larger compound libraries and the application
to other disease models.
The end-stage of Alzheimer disease (AD) is marked by extracellular plaques of amyloid peptide Aß, neurofibrillary tangles composed of hyperphosphorylated 
-protein and the decreased density of cholinergic neurons in the basal forebrain (40). The major component of the extracellular amyloid deposits is the 40–42 amino acid ß-amyloid (Aß), the product of proteolytic cleavage of the much larger amyloid ß precursor protein APP (40). Both APP and the MAP are substrates of glycogen synthase kinase 3 (GSK3ß), a protein which plays a major role not only in neurodegenerative disease but also in Wnt and Sonic hedgehog signaling (41). Two different genes encode for GSK3 and GSK3ß, a splice variant of which, GSK3ß2, is expressed in the brain (41). GSK3s play a part in regulation of the cell-division cycle, stem-cell renewal and differentiation, apoptosis, circadian rhythm, transcription and insulin action. This makes them interesting drug targets for diseases as diverse as neurodegenerative disease, bipolar affective disorder and diabetes (42). The GSK3 family is highly conserved throughout evolution and specific inhibition of GSK3ß, for example, could potentially manipulate the kinesin-driven vesicle transport in neurons. Reduction of GSK3ß activity levels by siRNAs or known inhibitors such as lithium and kenpaullone (25) decreased amyloid-ß production in cultured cell lines (43–45). In Drosophila, GSK3ß inhibition reverses vesicle aggregation caused by overexpression of that is associated with loss of locomotor function (46). This finding not only implicates GSK3ß inhibitors as useful candidates for the treatment of neurodegenerative diseases but also suggests that the effects of are dependent on its phosphorylation state. To date, over 30 GSK3 inhibitors are known, most of which bind in the ATP-binding pocket (42) (for representative examples refer to Table 2). Almost all GSK3ß inhibitors share a low molecular weight (<600) and flat, hydrophobic heterocycles comprising part of their structures. Binding is mediated predominantly through hydrophobic interactions with commonly two to three hydrogen bonds for spatial orientation. Most of these inhibitors compete with ATP in the ATP-binding site of the kinase. However, monovalent lithium ions compete directly with divalent magnesium ions, impairing kinase activity. Although ATP-binding sites of kinases are remarkably similar, there are numerous examples of selective inhibition of a specific kinase by interaction with the ATP-binding pocket (47). However, a major drawback is that most of the current GSK3ß inhibitors also exhibit an affinity for other kinases, thereby reducing the specificity and their potential as therapeutic compounds. Kenpaullone (25) is also a known inhibitor for cyclin-dependent kinases and therefore affects progression through the cell cycle. In addition, the indirect reduction of GSK3 activity levels by the regulation of the intracellular localization of GSK3 or interference with the interaction of GSK3 with scaffold proteins or downstream targets could represent viable routes for drug discovery as well (48). Although it has been difficult to develop inhibitors of protein–protein interactions in the past, recent work on the inhibition of the interaction between MDM2 and p53 has demonstrated that this strategy is feasible, at least in some cases (49).
Both Aß and kinesin light chains, as well as
, are
substrates of GSK3ß. Thus, increased GSK3ß
activity does not only lead to increased levels of Aß
and phosphorylated kinesin light chains, it can also cause hyperphosphorylation
of
which is expressed predominantly in neurons of the central
nervous system.
is thought to play a role in the assembly and
stabilization of neuronal microtubules, as well as in organelle
transport along axons and dendrites. Overall,
seems to be implicated
in several neurodegenerative diseases, especially those including
parkinsonism or dementia (50
–52
). The sequestrations of
hyperphosphorylated
-protein are key features of human tauopathies.
In addition, tauopathies are marked by filamentous
-inclusions,
reduced numbers of microtubules, impaired fast axonal transport
(FAT), neurodegeneration and motor weakness. These hallmarks
are recapitulated in a transgenic PrP T44 mouse model which
expresses the shortest human
-isoform T44 under the control
of the mouse prion protein promoter PrP (53
,54
). A recent study
tested the hypothesis that microtubule-stabilizing drugs might
find a therapeutic application in human tauopathies by attenuating
the loss of normal
functions that results from
-sequestration
into tangles (55
). Previous
in vitro studies had shown already
that microtubule-binding substances such as Taxol mitigate Aß-induced
neuronal death and
-phosphorylation (56
). Indeed, Paclitaxel
(
2), a microtubule stabilizing compound administered commonly
in cancer chemotherapy, was able to correct the FAT deficit
in the PrP T44 Tg mouse model (55
). Moreover, an increased number
of microtubules and amelioration of motor impairments in mice
could be observed. These results provide a mechanistic link
of tauopathies and impairment of microtubule stability. Markedly,
no changes in the abundance of spinal chord
-spheroids have
been observed. Consequently, the motor and FAT impairment related
to human tauopathies do not seem to depend on the attenuation
of aggresome formation. The mitigation of the FAT phenotype
in PrP T44 mice demonstrates a form of
in vivo therapy that
corrects loss-of-function rather than correcting the gain-of-function
of disease proteins. However, because of the central role of
microtubule in a wide variety of disease processes, therapeutic
microtubules stabilization will almost certainly have to be
combined with more specific emerging therapies for Alzheimer
or other human tauopathies.
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CONCLUDING REMARKS
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The central role of microtubules and microtubular transport
makes them an appealing target in selective drug development.
All currently marketed drugs that affect microtubules disrupt
microtubular dynamics without any specificity for diseased cells.
Interference with microtubular dynamics will trigger apoptosis
and thus cause cell death mainly in rapidly dividing cells such
as cancer cells. Considering the serious and sometimes life-threatening
side effects, only rare (or perhaps desperate) circumstances
would justify similarly harsh therapeutic regimens. Future drugs
will have to offer higher selectivity and specificity, which
translates into fewer side effects and better patient compliance.
Moreover, defects of microtubular or intraflagellar transport
will have to target specific parts of the transport machinery
to avoid interference with other pathways. Specific inhibitors
of GSK3ß have such potential with implications in
neurodegenerative diseases, mood disorders and diabetes (42
).
The mechanism of action of monastrol (17) differs from known cancer treatments and may provide advantages in the treatment of multi-drug resistant cancer cell lines. At present, there are several derivatives undergoing clinical trials. Monastrol (17) represents the first selective inhibition of a specific motor protein (13). The inhibition of Eg5 specifically will prove useful for further investigations of its role in cellular processes. It also demonstrated that despite considerable sequence homology between members of the kinesin protein family, it is possible to find and develop selective inhibitors for a single motor protein. Similarly, the selective inhibition of the -tubulin deacetylase activity of histone deacetylases will allow further investigation of the role of -tubulin acetylation in cellular processes (22). Finally, the interplay between chemistry and cell biology, suggesting that HDAC6 is the link between polyubiquitinated misfolded proteins and dynein transport, exemplifies the future research at the interface between these two disciplines. The combination of methods of both fields has driven investigation of incompletely understood cellular processes, such as aggresome formation, and has facilitated further investigations of the role of HDAC6 in the cell. In addition, closer collaboration at the interface of biology and chemistry facilitates and accelerates the identification of bioactive compounds. By combining both in vitro and in vivo assays, the problem of bioavailability is factored into the process of lead identification (38). Moreover, cell- or even tissue-based assays can be employed for both lead and target identifications.
Although a great demand for more selective small molecule effectors targeting specific pathological processes remains, new combination therapies might fill the need for some well-characterized diseases. The use of classical cancer drugs in lower doses for the treatment of Alzheimer disease attenuates one aspect of the disease pathology, the impairment of FAT (55). Combination with kinase inhibitors, for example, to mitigate the hyperphosphorylation phenotype could serve as a new therapeutic regimen for AD patients. Similarly, many known drugs or bioactive molecules in combination could prove effective in entirely different clinical implications by targeting similar pathological mechanisms. So, while lacking a specific and singular target (e.g. for Alzheimer disease), the oligo-factorial approach utilizing bioactive molecules targeting several aspects of processes known to be involved in pathogenesis is potentially able to fill the need for treatment.
Ciliary dysfunction has been linked to several human diseases including Retinitis pigmentosa (RP), polycystic kidney disease (PKD), as well as the human obesity syndrome Bardet–Biedl syndrome (5,57). The close connection between microtubules and ciliary function indicates that small molecule effectors targeting microtubules might also be implicated in the treatment of such diverse diseases as RP or obesity.
With the emerging role of microtubule-associated processes in human disease, the synthesis and discovery of small molecules modulating these processes will evolve rapidly. Improved selectivity will necessitate a more focused mechanism of function than that of hitherto known microtubule effectors. In the light of the recent successful inhibition of the protein–protein interaction between MDM2 and p53 (49), the directed manipulation of such interactions between microtubules and their associated proteins has become possible. Further investigations in this field of interdisciplinary research will certainly address this question.
Conflict of Interest statement. None declared.
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