Development of Cdc2-like Kinase 2 Inhibitors: Achievements and Future Directions

Abstract

Cdc2-like kinases (CLKs; CLK1–4) are associated with various neurodegenerative disorders, metabolic regulation, and viral infection and have been recognized as potential drug targets. Human CLK2 has received increasing attention as a regulator that phosphorylates serine- and arginine-rich (SR) proteins and subsequently modulates the alternative splicing of precursor mRNA (pre-mRNA), which is an attractive target for degenerative disease and cancer. Numerous CLK2 inhibitors have been identified, with several molecules currently in clinical development. The first CLK2 inhibitor Lorecivivint (compound 1) has recently entered phase 3 clinical trials. However, highly selective CLK2 inhibitors are rarely reported. This Perspective summarizes the biological roles and therapeutic potential of CLK2 along with progress on the development of CLK2 inhibitors and discusses the achievements and future prospects of CLK2 inhibitors for therapeutic applications.

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

“…Tol, known as tolerance, is the radius of the pharmacophoric feature sphere. S(disp/tol) 2 is the summation of (disp/tol) 2 values for all pharmacophoric features that successfully map corresponding chemical functionalities in the tted compound. [10][11][12][13][14][15][16][17][18][19][20]42,43 Additional 166 physicochemical descriptors that included numerous physicochemical, topological and ngerprint descriptors 55,56 were also calculated employing the "Calculate Molecular Properties" protocol implemented within Discovery Studio (version 4.5, BIOVIA, USA).…”

“… 1 Cyclin dependent-like family kinases (Cdc2-like protein kinases) are dual specific kinases that have been shown to regulate mRNA splicing by phosphorylation of serine and arginine rich proteins. 2 The Cdc2-like kinases family (CLK) consists of four isoforms CLK1–4 exhibiting the typical protein kinase folds and possessing different lengths of amino acids and they are involved in alternative splicing and RNA processing in Duchenne muscular dystrophy, Alzheimer's disease, HIV-1, influenza virus and cancer. 3 CLK4 inhibition has recently raised interest as a potential treatment for different CLK4-over expressing cancer types, i.e.…”

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

“… 93 CLK2 is closely associated with many neurodegenerative diseases, metabolic diseases, and viral infection‐related diseases, and is considered as a potential drug target for these diseases. 94 Its specific inhibitory drugs are used in the experimental treatment of Alzheimer's disease, insulin resistance, and neoplasms, especially leukemia and triple‐negative breast cancer. 95 , 96 It is reported that the first CLK2 inhibitor, lorecivivint, has entered phase III clinical trials in recent years.…”

“… 95 , 96 It is reported that the first CLK2 inhibitor, lorecivivint, has entered phase III clinical trials in recent years. 94 We look forward to the therapeutic prospects of CLK2 inhibitors.…”

“…The CLK2 kinase family is regulated by the AKT and PI3K kinase families, and controls the ATR and the PKC families 93 . CLK2 is closely associated with many neurodegenerative diseases, metabolic diseases, and viral infection‐related diseases, and is considered as a potential drug target for these diseases 94 . Its specific inhibitory drugs are used in the experimental treatment of Alzheimer's disease, insulin resistance, and neoplasms, especially leukemia and triple‐negative breast cancer 95,96 .…”