首页|Identification of harmine and beta-carboline analogs from a high-throughput screen of an approved drug collection; profiling as differential inhibitors of DYRK1A and monoamine oxidase A and for in vitro and in vivo anti-cancer studies

Identification of harmine and beta-carboline analogs from a high-throughput screen of an approved drug collection; profiling as differential inhibitors of DYRK1A and monoamine oxidase A and for in vitro and in vivo anti-cancer studies

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  • NSTL
  • Elsevier
DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1a) is highly expressed in glioma, an aggressive brain tumor, and has been proposed as a therapeutic target for cancer. In the current study, we have used an optimized and validated time-resolved fluorescence energy transfer (TR-FRET)-based DYRK1A assay for high-throughput screening (HTS) in 384-well format. A small-scale screen of the FDA-approved Prestwick drug collection identified the beta-carboline, harmine, and four related analogs as DYRK1A inhibitors. Hits were confirmed by dose response and in an orthogonal DYRK1A assay. Harmine's potential therapeutic use has been hampered by its off-target activity for monoamine oxidase A (MAO-A) which impacts multiple nervous system targets. Selectivity profiling of harmine and a broader collection of analogs allowed us to map some divergent SAR (structure-activity relationships) for the DYRK1A and MAO-A activities. The panel of harmine analogs had varying activities in vitro in glioblastoma (GBM) cell lines when tested for anti-proliferative effects using a high content imaging assay. In particular, of the identified analogs, harmol was found to have the best selectivity for DYRK1A over MAO-A and, when tested in a glioma tumor xenograft model, harmol demonstrated a better therapeutic window compared to harmine.

DYRK1Aharmineharmolhigh throughput screeningmonoamine oxidase Ahedgehogglioma

Tarpley, Michael、Oladapo, Helen O.、Strepay, Dillon、Caligan, Thomas B.、Chdid, Lhoucine、Shehata, Hassan、Roques, Jose R.、Thomas, Rhashad、Laudeman, Christopher P.、Onyenwoke, Rob U.、Darr, David B.、Williams, Kevin P.

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North Carolina Cent Univ, Biomfg Res Inst, Durham, NC 27707 USA

North Carolina Cent Univ, Dept Biol & Biomed Sci, Durham, NC 27707 USA

Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27514 USA

North Carolina Cent Univ, Dept Pharmaceut Sci, 1801 Fayetteville St, Durham, NC 27707 USA

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2021

10.1016/j.ejps.2021.105821

European journal of pharmaceutical sciences

European journal of pharmaceutical sciences

ISTP
ISSN：0928-0987
年,卷(期)：2021.162
  • 9
  • 115