Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.

TitleIdentification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.
Publication TypeJournal Article
Year of Publication2024
AuthorsMadasu, C, Liao, Z, Parks, SE, Sharma, KL, Bohren, KM, Ye, Q, Li, F, Palaniappan, M, Tan, Z, Yuan, F, Creighton, CJ, Tang, S, Masand, RP, Guan, X, Young, DW, Monsivais, D, Matzuk, MM
JournalProc Natl Acad Sci U S A
Volume121
Issue19
Paginatione2322934121
Date Published2024 May 07
ISSN1091-6490
KeywordsCell Movement, DNA, Endometriosis, Female, Humans, Protein Kinase Inhibitors, Receptor, EphA2, Receptors, Eph Family, Small Molecule Libraries
Abstract

EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface-associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that and expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value. We screened DNA-encoded chemical libraries (DECL) to rapidly identify EPHA2/4 kinase inhibitors. Hit compound, CDD-2693, exhibited picomolar/nanomolar kinase activity against EPHA2 (K: 4.0 nM) and EPHA4 (K: 0.81 nM). Kinome profiling revealed that CDD-2693 bound to most EPH family and SRC family kinases. Using NanoBRET target engagement assays, CDD-2693 had nanomolar activity versus EPHA2 (IC: 461 nM) and EPHA4 (IC: 40 nM) but was a micromolar inhibitor of SRC, YES, and FGR. Chemical optimization produced CDD-3167, having picomolar biochemical activity toward EPHA2 (K: 0.13 nM) and EPHA4 (K: 0.38 nM) with excellent cell-based potency EPHA2 (IC: 8.0 nM) and EPHA4 (IC: 2.3 nM). Moreover, CDD-3167 maintained superior off-target cellular selectivity. In 12Z endometriotic epithelial cells, CDD-2693 and CDD-3167 significantly decreased EFNA5 (ligand) induced phosphorylation of EPHA2/4, decreased 12Z cell viability, and decreased IL-1β-mediated expression of prostaglandin synthase 2 (). CDD-2693 and CDD-3167 decreased expansion of primary endometrial epithelial organoids from patients with endometriosis and decreased Ewing's sarcoma viability. Thus, using DECL, we identified potent pan-EPH inhibitors that show specificity and activity in cellular models of endometriosis and cancer.

DOI10.1073/pnas.2322934121
Alternate JournalProc Natl Acad Sci U S A
PubMed ID38701119
PubMed Central IDPMC11087803
Grant ListR33 HD099995 / HD / NICHD NIH HHS / United States
R01 HD105800 / HD / NICHD NIH HHS / United States
R01 HD110038 / HD / NICHD NIH HHS / United States
K99 HD096057 / HD / NICHD NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
R03 CA259664 / CA / NCI NIH HHS / United States
R00 HD096057 / HD / NICHD NIH HHS / United States

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