Language
English
Publication Date
11-19-2024
Journal
Proceedings of the National Academy of Sciences of the United States of America
DOI
10.1073/pnas.2413108121
PMID
39541346
PMCID
PMC11588046
PubMedCentral® Posted Date
11-14-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Activin receptor type 1 (ACVR1; ALK2) and activin receptor like type 1 (ACVRL1; ALK1) are transforming growth factor beta family receptors that integrate extracellular signals of bone morphogenic proteins (BMPs) and activins into Mothers Against Decapentaplegic homolog 1/5 (SMAD1/SMAD5) signaling complexes. Several activating mutations in ALK2 are implicated in fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine gliomas, and ependymomas. The ALK2 R206H mutation is also present in a subset of endometrial tumors, melanomas, non-small lung cancers, and colorectal cancers, and ALK2 expression is elevated in pancreatic cancer. Using DNA-encoded chemistry technology, we screened 3.94 billion unique compounds from our diverse DNA-encoded chemical libraries (DECLs) against the kinase domain of ALK2. Off-DNA synthesis of DECL hits and biochemical validation revealed nanomolar potent ALK2 inhibitors. Further structure-activity relationship studies yielded center for drug discovery (CDD)-2789, a potent [NanoBRET (NB) cell IC
Keywords
Humans, Activin Receptors, Type I, Protein Kinase Inhibitors, Activin Receptors, Type II, DNA, Drug Discovery, Small Molecule Libraries, Signal Transduction, DEL, kinase inhibitors, X-ray Crystallography
Published Open-Access
yes
Recommended Citation
Jimmidi, Ravikumar; Monsivais, Diana; Ta, Hai Minh; et al., "Discovery of Highly Potent and ALK2/ALK1 Selective Kinase Inhibitors Using DNA-Encoded Chemistry Technology" (2024). Faculty and Staff Publications. 3845.
https://digitalcommons.library.tmc.edu/baylor_docs/3845