The cytoskeleton is a complex network of protein filaments that provides structural support and plays a vital role in cellular processes, such as cell division, migration, and intracellular transport. Disruptions in the structures of microtubules and proteins associated with them are inherent to various diseases, including cancer, neurodegenerative disorders, cardiovascular diseases, and certain genetic diseases.
Several classes of cytoskeleton-targeting molecules, such as microtubule-targeting agents, actin modulators and myosin regulators, have been reported to show therapeutic potential, particularly with respect to cancer and cardiovascular diseases. As a result, drug discovery campaigns focused on the molecules under consideration hold a great potential for the development of novel drugs.
Providing cutting-edge tools and solutions for cytoskeleton-focused drug discovery research, our cheminformatics team has developed this novel Screening Set of over 11,000 drug-like screening compounds that potentially target and modulate the cytoskeleton. These structurally-diverse small molecules were selected with a 2D fingerprint similarity search against the proprietary HTS Compound Collection.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Figure 1. The compounds target microtubule-associated proteins.
Background Information
The cytoskeleton is a dynamic complex of interconnected filamentous protein structures found in plant, animal, bacterial, and archaeal cells. The cytoskeleton of all cells consists of three main components: microtubules, microfilaments, and intermediate filaments [1]. Each of these components has a specific composition and function.
Microtubules consist of alpha- and beta-tubulin [2]. They are involved in many important functions, for example, in the formation of the mitotic spindle, creating axonemes of cilia and flagella, intracellular transport, etc [3], [4].
Intermediate filaments can contain different proteins depending on their localization and function. For example, those made of vimentins are found in mesenchymal cells
[5]; the ones made of keratin are available in epithelial cells [6]; those built by lamin provide strength to the nuclear envelope [7]; and at last, the filaments formed by desmin give structural and mechanical support to muscle cells [8]. A special type of intermediate filaments is known as neurofilaments [9], which are found in nervous tissue cells. Intermediate filaments are established to perform the main structural function in cells [10].
Microfilaments are made of actin. The key roles of microfilaments are muscle contraction, cell movement, intracellular transport, and participation in cytokinesis [11]. 
Microfilaments are involved in the initial stages of carcinogenesis by regulating the expression of oncogenes and inhibiting apoptosis [13]. Vimentin intermediate filaments play an important role in the development of infectious lung diseases, as well as in the development of malignant and benign lung tumors [14]. Intermediate filaments are also tumor markers [15].
The cytoskeleton presents a rich source of molecular targets for drug discovery. Microtubule-targeting agents (MTAs) interfere with microtubule assembly and disassembly dynamics. Drugs, like taxanes (e.g., paclitaxel) and vinca alkaloids (e.g., vincristine), have successfully been developed as anticancer agents, primarily by disrupting mitosis and inhibiting cell division. Actin polymerization inhibitors, such as cytochalasins and latrunculins, have shown potential in controlling cell migration and invasion, making them promising candidates for cancer metastasis intervention. Small molecules that modulate myosin motor protein activity have been investigated for their therapeutic capabilities in some conditions, including hypertension, heart failure and smooth muscle disorders.
Compound selection
Our reference set of known epigenetic modulator molecules was obtained from the ChEMBL database. The set included all available compounds with high experimental activity toward human cytoskeleton targets. Subsequently, a 2D fingerprint similarity search was conducted against the Life Chemicals HTS Compound Collection, using a Tanimoto index threshold of ≥ 0.85. The resulting Screening Library of over 11,000 cytoskeleton-related screening compounds does not contain PAINS, toxic and reactive molecules, ensuring the selection of safe and relevant compounds.
Among the selected compounds, there are prospective inhibitors of the following cytoskeleton-specific molecular targets:
- AMP-activated protein kinase, AMPK
- Cytochrome P450 2C9
- MAP kinase ERK2
- MAP kinase-activated protein kinase 2
- MAP kinase-activated protein kinase 5
- Dynamin-2
- Mitogen-activated protein kinase
- Microtubule-associated protein tau
- c-Jun N-terminal kinase 3
- Replicase polyprotein 1ab
- Ribosomal protein S6 kinase alpha 1
- Casein kinase I delta
- Dynamin-1
- Prelamin-A/C
- MAP kinase p38 alpha
- Ribosomal protein S6 kinase alpha 3
- Kinesin-like protein 1
- c-Jun N-terminal kinase 1
- c-Jun N-terminal kinase 2
- Cyclin-dependent kinase 5/CDK5 activator 1
- Mitochondrial import inner membrane translocase subunit TIM23
- Mitogen-activated protein kinase; ERK1/ERK2
- MAP kinase signal-integrating kinase 2
- MAP kinase p38 beta
- Cytochrome P450
- Tubulin
- Matrix metalloproteinase 7
- Fascin
- Caspase-9
- Cyclin-dependent kinase 5
- MAP kinase p38
- MAP kinase-interacting serine/threonine-protein kinase MNK1
- Methionine aminopeptidase 2
- MAP kinase ERK1
- c-Jun N-terminal kinase, JNK
- Mitogen-activated protein kinase kinase kinase kinase 4
- Mitogen-activated protein kinase kinase kinase 5
- Mitogen-activated protein kinase kinase kinase kinase 5
- Casein kinase I isoform alpha/delta
- Misshapen-like kinase 1
- Dual specificity mitogen-activated protein kinase kinase 1
- Caspase-8
- Multidrug resistance-associated protein 4
- Kinesin-1 heavy chain
- Hepatocyte growth factor receptor
- Alpha-glucosidase MAL62
- MAP/microtubule affinity-regulating kinase 2
- Mitogen-activated protein kinase 7
- Ribosomal protein S6 kinase alpha 2
- Tau-tubulin kinase 1
- MAP kinase p38 delta
- Voltage-gated potassium channel subunit Kv7.1/Misshapen-like kinase 1
- Serine/threonine-protein kinase RAF and Dual specificity mitogen-activated protein kinase kinase 1 (Raf/MEK)
- Tubulin beta chain
- Kinesin-1 heavy chain/ Tyrosine-protein kinase receptor RET
- AMP-activated protein kinase, alpha-1 subunit
- Mitogen-activated protein kinase kinase kinase kinase 2
- Dual specificity protein kinase TTK
- Actin-related protein 2
- Tubulin alpha-1 chain
- Glycogen synthase kinase-3
- Mitogen-activated protein kinase 6
- Dual specificity protein phosphatase 6
- Tubulin beta
- Methionine aminopeptidase
- Dual specificity mitogen-activated protein kinase kinase 4
References:
- Pegoraro AF, Janmey P, Weitz DA. Mechanical Properties of the Cytoskeleton and Cells. Cold Spring Harb Perspect Biol. 2017;9(11):a022038. Published 2017 Nov 1.
- Kapoor V, Hirst WG, Hentschel C, Preibisch S, Reber S. MTrack: Automated Detection, Tracking, and Analysis of Dynamic Microtubules. Sci Rep. 2019;9(1):3794.
- Goodson HV, Jonasson EM. Microtubules and Microtubule-Associated Proteins. Cold Spring Harb Perspect Biol. 2018;10(6):a022608.
- Logan CM, Menko AS. Microtubules: Evolving roles and critical cellular interactions. Exp Biol Med (Maywood). 2019;244(15):1240-1254.
- Battaglia RA, Delic S, Herrmann H, Snider NT. Vimentin on the move: new developments in cell migration. F1000Res. 2018;7:F1000 Faculty Rev-1796.
- Yoon S, Leube RE. Keratin intermediate filaments: intermediaries of epithelial cell migration. Essays Biochem. 2019;63(5):521-533.
- Cenni V, Capanni C, Mattioli E, et al. Lamin A involvement in ageing processes. Ageing Res Rev. 2020;62:101073.
- Agnetti G, Herrmann H, Cohen S. New roles for desmin in the maintenance of muscle homeostasis. FEBS J. 2022;289(10):2755-2770.
- Yuan A, Rao MV, Veeranna, Nixon RA. Neurofilaments and Neurofilament Proteins in Health and Disease. Cold Spring Harb Perspect Biol. 2017;9(4):a018309.
- Eldirany SA, Lomakin IB, Ho M, Bunick CG. Recent insight into intermediate filament structure. Curr Opin Cell Biol. 2021;68:132-143.
- Svitkina T. The Actin Cytoskeleton and Actin-Based Motility. Cold Spring Harb Perspect Biol. 2018;10(1):a018267.
- Ilan Y. Microtubules: From understanding their dynamics to using them as potential therapeutic targets. J Cell Physiol. 2019;234(6):7923-7937.
- Izdebska M, Zielińska W, Hałas-Wiśniewska M, Grzanka A. Involvement of Actin and Actin-Binding Proteins in Carcinogenesis. Cells. 2020;9(10):2245.
- Surolia R, Antony VB. Pathophysiological Role of Vimentin Intermediate Filaments in Lung Diseases. Front Cell Dev Biol. 2022;10:872759.
- Sharma P, Alsharif S, Fallatah A, Chung BM. Intermediate Filaments as Effectors of Cancer Development and Metastasis: A Focus on Keratins, Vimentin, and Nestin. Cells. 2019;8(5):497.