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. Author manuscript; available in PMC: 2020 Feb 21.
Published in final edited form as: Cell Chem Biol. 2018 Dec 6;26(2):213–222.e6. doi: 10.1016/j.chembiol.2018.10.019

Figure 5. Attachment of a zinc-chelating moiety biases the replication-promoting activity of GNF-4877 toward zinc-rich β-cells.

Figure 5.

(A) DYRK1A binding affinity of GNF-4877, 4877-EXT-DPA, and 4877-EXT-DBA (n=2 per concentration). (B) Dose response curves for GNF-4877, 4877-EXT-DPA, and 4877-EXT-DBA based on DYRK1A inhibition via a luciferase reporter in transfected HEK 293T cells (n=4 per concentration). (C) Representative images of dispersed rat islet cultures treated with 4877-EXT-DBA (3 μM) (top) or 4877-EXT-DPA (3 μM) (bottom) and stained (PDX-1, Insulin, and Ki-67). White arrows indicate replicating β-cells, yellow arrows indicate replicating non-β-cells. (D) Replication induced by DMSO, GNF-4877 (1–5 μM), 4877-EXT-DBA (3 μM), and 4877-EXT-DPA (3 μM) in co-cultured PDX-1 positive β-cells (blue) and non-β-cells (red). Data are pooled from two independent experiments of two rats each (n=8–11). (E) β-cell selectivity for the experiment in (D), defined as the ratio of β-cell replication to non-β-cell replication (n=8–11). (F) Human islet replication induction by DMSO, GNF-4877 (1–5 μM), 4877-EXT-DBA (3.3–10 μM), and 4877-EXT-DPA (3.3–10 μM). Data represent two donors in two independent experiments (n=17–25). (G) β-cell selectivity for human islets in (F). Data represent five pooled donors in five independent experiments (n=17–25). Data are represented as mean ± S.D.

See also Figure S5.