Flavopiridol (Alvocidib), a Cyclin-dependent Kinases (CDKs) Inhibitor, Found Synergy Effects with Niclosamide in Cutaneous T-cell Lymphoma

Abstract

Flavopiridol (FVP; Alvocidib), a CDKs inhibitor, is currently undergoing clinical trials for treatment of leukemia and other blood cancers. Our studies demonstrated that FVP also inhibited p38 kinases activities with IC 50 (µM) for p38α: 1.34; p38 β: 1.82; p38γ: 0.65, and p38δ: 0.45. FVP showed potent cytotoxicity in cutaneous T-cell lymphoma (CTCL) Hut78 cells, with IC 50 <100 nM. NMR analysis revealed that FVP bound to p38γ in the ATP binding pocket, causing allosteric perturbation from sites surrounding the ATP binding pocket. Kinomic profiling with the PamGene platform in both cell-based and cell-free analysis further revealed dosage of FVP significantly affects downstream pathways in treated CTCL cells, which suggested a need for development of synergistic drugs with FVP to prevent its clinically adverse effects. It led us discover niclosamide as a synergistic drug of FVP for our future in vivo study.

Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis

“…Alvocidib, a synthetic flavonoid compound deriving from an extract of an Indian plant, exhibits ability to inhibit cyclin-dependent kinases, resulting in cell division arrest and induction of apoptosis. 76 Herein, it showed potential in reversing the plasma cell-mediated molecular signature. To this end, dysregulation patterns within the “plasma cells” module revealed merit for a plethora of cytotoxic drugs, such as daunorubicin, doxorubicin, and etoposide.…”

Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors

“…[ 87 , 88 ]. NCS functions also as a STAT3 inhibitor, useful to enhance the efficacy of diverse types of cytotoxic drugs and targeted therapeutics [ 89 , 90 , 91 ].…”

Novel pyrimidine Schiff bases and their selenium-containing nanoparticles as dual inhibitors of CDK1 and tubulin polymerase: design, synthesis, anti-proliferative evaluation, and molecular modelling

“…This explains why CDK1 inhibitors are essential therapeutic targets when designing anti-proliferative agents. Structurally, CDK1 inhibitors are of various central cores, including; flavones 7 , benzimidazoles 8 , and thiazolones 9 . Furthermore, pyrimidines represent strategic motifs in many CDK1 inhibitors, with high activity and IC 50 values in the nanomolar range, including dinaciclib ( I ) 10 , roscovitine ( II ) 11 , and CGP74514A ( III ) 12 , as examples of purines and purine isosteres.…”