Novel selective thiadiazine DYRK1A inhibitor lead scaffold with human pancreatic β-cell proliferation activity

European Journal of Medicinal Chemistry
Kunal KumarRobert J DeVita

Abstract

The Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) is an enzyme that has been implicated as an important drug target in various therapeutic areas, including neurological disorders (Down syndrome, Alzheimer's disease), oncology, and diabetes (pancreatic β-cell expansion). Current small molecule DYRK1A inhibitors are ATP-competitive inhibitors that bind to the kinase in an active conformation. As a result, these inhibitors are promiscuous, resulting in pharmacological side effects that limit their therapeutic applications. None are in clinical trials at this time. In order to identify a new DYRK1A inhibitor scaffold, we constructed a homology model of DYRK1A in an inactive, DFG-out conformation. Virtual screening of 2.2 million lead-like compounds from the ZINC database, followed by in vitro testing of selected 68 compounds revealed 8 hits representing 5 different chemical classes. We chose to focus on one of the hits from the computational screen, thiadiazine 1 which was found to inhibit DYRK1A with IC50 of 9.41 μM (Kd = 7.3 μM). Optimization of the hit compound 1, using structure-activity relationship (SAR) analysis and in vitro testing led to the identification of potent thiadiazine analogs with signifi...Continue Reading

Citations

Feb 14, 2020·Science Translational Medicine·Courtney AckeifiAndrew F Stewart
Apr 29, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kunal KumarRobert J DeVita
Sep 23, 2020·International Journal of Molecular Sciences·Hye Ree YoonNam Sook Kang
Dec 20, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Anne WurzlbauerFranz Bracher
Mar 9, 2021·Journal of Medicinal Chemistry·Kunal KumarRobert J DeVita
Apr 18, 2021·Cell Death Discovery·Ariadna RecasensLenka Munoz
Jun 29, 2021·Bioorganic & Medicinal Chemistry Letters·Areum ParkHyuk Lee
Aug 3, 2021·Evidence-based Complementary and Alternative Medicine : ECAM·Akurange Sujeevi Dammadinna WickramasingheAnoja Priyadarshani Attanayake
Aug 28, 2021·International Journal of Molecular Sciences·Stefania DemuroAndrea Cavalli

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