Discovery of new Cdc2-like kinase 4 (CLK4) inhibitors <i>via</i> pharmacophore exploration combined with flexible docking-based ligand/receptor contact fingerprints and machine learning

Al-Tawil, Mai Fayiz; Daoud, Safa; Hatmal, Ma’mon M.; Taha, Mutasem O.

doi:10.1039/d2ra00136e

Cited by 10 publications

(5 citation statements)

References 62 publications

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“…It is noteworthy that certain CLKs inhibitors were recognized as ideal lead compounds for structural optimization to obtain more specific CLKs inhibitors. Moreover, a genetic function algorithm support vector regression (GFA-SVR) 171 and ligand- or structure-based drug optimization 172 , 173 provided predictive models and effective methods for screening and optimizing of the potential of CLKs inhibitors. Nonetheless, research on CLKs-based therapy is still in the initial stage; the cognition and development of CLKs inhibitors will undoubtedly progress upon more in-depth investigation.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Cdc2-like kinases: structure, biological function, and therapeutic targets for diseases

Song

Pang

Zhang

et al. 2023

Sig Transduct Target Ther

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The CLKs (Cdc2-like kinases) belong to the dual-specificity protein kinase family and play crucial roles in regulating transcript splicing via the phosphorylation of SR proteins (SRSF1–12), catalyzing spliceosome molecular machinery, and modulating the activities or expression of non-splicing proteins. The dysregulation of these processes is linked with various diseases, including neurodegenerative diseases, Duchenne muscular dystrophy, inflammatory diseases, viral replication, and cancer. Thus, CLKs have been considered as potential therapeutic targets, and significant efforts have been exerted to discover potent CLKs inhibitors. In particular, clinical trials aiming to assess the activities of the small molecules Lorecivivint on knee Osteoarthritis patients, and Cirtuvivint and Silmitasertib in different advanced tumors have been investigated for therapeutic usage. In this review, we comprehensively documented the structure and biological functions of CLKs in various human diseases and summarized the significance of related inhibitors in therapeutics. Our discussion highlights the most recent CLKs research, paving the way for the clinical treatment of various human diseases.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Cdc2-like kinases: structure, biological function, and therapeutic targets for diseases

Song

Pang

Zhang

et al. 2023

Sig Transduct Target Ther

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“…We have imported the experimentally-determined 3D structures of 5-HT2C and CLK4-KD proteins from the Protein Data Bank (PDB) [53]. The structure of 5-HT2C (PDB: 6BQH) is in complex with ritanserin in the binding site, while CLK4-KD (PDB: 6FYV) is in complex with 5-[(3-chlorophenyl)amino]benzo[c]- [2,6]naphthyridine-8-carboxylic acid (3NG) compound in the binding site [27,42]. The grid parameters were created to only include the proteins binding sites; they are shown in Table I.…”

Section: Molecular Docking Approachmentioning

confidence: 99%

“…One of these CLKs isoforms CLK4-KD is involved in the phosphorylation of serine, arginine, threonine and tyrosine residues and is crucial in the control of fundamental cellular activities. This kinase may be a target for several diseases, including cancer, Duchenne muscular dystrophy, inflammatory and viral diseases, or neurodegenerative diseases [2,16,38,40,51]. Despite these considerations, just a few numbers of computer-aided molecular design and discovery studies focused on CLK4 and 5-HT2C receptors modulators were reported.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Novel Carprofen Derivatives as Inhibitors of the Serotonin 5-Ht2c Receptors and Clk4-Kd Protein Kinase for the Development of Pharmacologically Active Compounds

UDREA

2023

FARMACIA

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In search of novel compounds with multiple biological activities, nine carprofen derivatives (1a-i) have been investigated by molecular docking to explore their interactions with target proteins involved in different diseases, from cancer to inflammation associated pathologies (viral infections, pain, neurodegenerative conditions). The docking studies have been performed to study the dual specificity for the protein kinase CLK4 and serotonin 2C (5-HT2C) receptor. Our molecular docking predictions indicate that the highest predicted binding energy has been observed in the case of the 1b derivative for the 5-HT2C receptor and respectively in the case of derivative 1h for CLK4-KD. Therefore, these two derivatives show a promising potential for the development of multi-pharmacologically active compounds. RezumatÎn vederea descoperirii de noi compuși cu activități biologice multiple, nouă derivați ai carprofenului (1a-i) au fost investigați prin andocare moleculară pentru a explora interacțiunile lor cu proteinele țintă implicate în diferite boli, de la cancer la patologii asociate inflamației (infecții virale, durere, afecțiuni neurodegenerative). Studiile de andocare au fost efectuate pentru a studia specificitatea duală pentru receptorul proteinkinazei CLK4 și cel al serotoninei 2C (5-HT2C). Predicțiile noastre de andocare moleculară indică faptul că cea mai mare energie de legare prezisă a fost observată în cazul derivatului 1b pentru receptorul 5-HT2C și, respectiv, în cazul derivatului 1h pentru receptorul CLK4-KD. Prin urmare, acești doi derivați arată un potențial promițător pentru dezvoltarea compușilor cu potențial farmacologic multivalent.

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“…[24][25][26] Clk4 is involved in alternative splicing and RNA processing in Duchenne muscular dystrophy, Alzheimer's disease, HIV-1, influenza virus. [27] Furthermore, its expression is correlated with poor patient survival in triple-negative breast cancer (TNBC) patients, also highly overexpressed in many types of cancer including lung, larynx, colon, rectum, melanomas, glioblastomas, and sarcomas. [26,28,29] Despite the importance of Clk4 in neurodegenerative diseases and cancer, it seems that no selective inhibitors targeting Clk4 have been reported.…”

Section: Introductionmentioning

confidence: 99%

N₁‐Benzoylated 5‐(4‐pyridinyl)indazole‐based kinase inhibitors: Attaining haspin and Clk4 selectivity via modulation of the benzoyl substituents

Aboelfotouh,

Abdallah,

Khalifa

et al. 2024

Archiv der Pharmazie

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Haspin and Clk4 are both understudied protein kinases (PKs), offering potential targets for the development of new anticancer agents. Thus, the identification of new inhibitors targeting these PKs is of high interest. However, the inhibitors targeting haspin or Clk4 developed to date show a poor selectivity profile over other closely related PKs, increasing the risk of side effects. Herein, we present two newly developed N1‐benzyolated 5‐(4‐pyridinyl)indazole‐based inhibitors (18 and 19), derived from a newly identified indazole hit. These inhibitors exhibit an exceptional inhibitory profile toward haspin and/or Clk4. Compound 18 (2‐acetyl benzoyl) showed a preference to inhibit Clk4 and haspin over a panel of closely related kinases, with sixfold selectivity for Clk4 (IC50 = 0.088 and 0.542 μM, respectively). Compound 19 (4‐acetyl benzoyl) showed high selectivity against haspin over the common off‐target kinases (Dyrks and Clks) with an IC50 of 0.155 μM for haspin. Molecular docking studies explained the remarkable selectivity of 18 and 19, elucidating how the new scaffold can be modified to toggle between inhibition of haspin or Clk4, despite the high homology of the ATP‐binding sites. Their distinguished profile allows these compounds to be marked as interesting chemical probes to assess the selective inhibition of haspin and/or Clk4.

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Discovery of new Cdc2-like kinase 4 (CLK4) inhibitors via pharmacophore exploration combined with flexible docking-based ligand/receptor contact fingerprints and machine learning

Abstract: Ligand-based pharmacophores, ligand–receptor contact fingerprints, physicochemical descriptors and machine learning were combined to probe binding of potent CLK4 antagonists. GFA-SVR gave the best model. Virtual screening identified 3 nanomolar hits.

Cited by 10 publications

References 62 publications

Cdc2-like kinases: structure, biological function, and therapeutic targets for diseases

Cdc2-like kinases: structure, biological function, and therapeutic targets for diseases

Characterization of Novel Carprofen Derivatives as Inhibitors of the Serotonin 5-Ht2c Receptors and Clk4-Kd Protein Kinase for the Development of Pharmacologically Active Compounds

N₁‐Benzoylated 5‐(4‐pyridinyl)indazole‐based kinase inhibitors: Attaining haspin and Clk4 selectivity via modulation of the benzoyl substituents

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Discovery of new Cdc2-like kinase 4 (CLK4) inhibitors via pharmacophore exploration combined with flexible docking-based ligand/receptor contact fingerprints and machine learning

Abstract: Ligand-based pharmacophores, ligand–receptor contact fingerprints, physicochemical descriptors and machine learning were combined to probe binding of potent CLK4 antagonists. GFA-SVR gave the best model. Virtual screening identified 3 nanomolar hits.

Cited by 10 publications

References 62 publications

Cdc2-like kinases: structure, biological function, and therapeutic targets for diseases

Cdc2-like kinases: structure, biological function, and therapeutic targets for diseases

Characterization of Novel Carprofen Derivatives as Inhibitors of the Serotonin 5-Ht2c Receptors and Clk4-Kd Protein Kinase for the Development of Pharmacologically Active Compounds

N1‐Benzoylated 5‐(4‐pyridinyl)indazole‐based kinase inhibitors: Attaining haspin and Clk4 selectivity via modulation of the benzoyl substituents

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N₁‐Benzoylated 5‐(4‐pyridinyl)indazole‐based kinase inhibitors: Attaining haspin and Clk4 selectivity via modulation of the benzoyl substituents