A Systematic Blueprint to Ligand the Proteome

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 68(2), P. 1090 - 1091

Published: Jan. 6, 2025

The Target 2035 initiative is an ambitious proposal to discover pharmacological tools across the human proteome. This Viewpoint summarizes approach inspired by that goal leveraging DNA-encoded library coupled with machine learning approaches assess ligandability of WD40 repeat target class proteins.

Language: Английский

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Enantioselective Protein Affinity Selection Mass Spectrometry (EAS-MS)

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

We report an enantioselective protein affinity selection mass spectrometry screening approach (EAS-MS) that enables the detection of weak binders, informs about selectivity, and generates orthogonal confirmation binding. After method development with control proteins, we screened 31 human proteins against a designed library 8,210 chiral compounds. 16 binders to 12 targets, including many predicted be "challenging ligand", were discovered confirmed in assays. 7 6 targets bound manner, K D s ranging from 3 20 µM. Binders for four (DDB1, WDR91, WDR55, HAT1) selected in-depth characterization using X-ray crystallography. In all cases, mechanism selectivity was readily explained. EAS-MS can used identify characterize selective weakly-binding ligands novel unprecedented throughput sensitivity.

Language: Английский

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Potent and selective SETDB1 covalent negative allosteric modulator reduces methyltransferase activity in cells

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 24, 2025

A promising drug target, SETDB1, is a dual methyl-lysine (Kme) reader and methyltransferase implicated in cancer neurodegenerative disease progression. To help understand the role of triple Tudor domain (3TD) its Kme reader, we first identify low micromolar potency small molecule ligand, UNC6535, which occupies simultaneously both TD2 TD3 binding sites. Further optimization leads to discovery UNC10013, covalent 3TD ligand targeting Cys385 SETDB1. UNC10013 potent with kinact/KI 1.0 × 106 M−1s−1 demonstrates proteome-wide selectivity. In cells, negative allosteric modulation SETDB1-mediated Akt methylation occurs after treatment UNC10013. Therefore, potent, selective, cell-active for demonstrating modulator properties making it tool study biological SETDB1 Design cysteine-targeting analogs reversible led high demonstrated inhibition approach therapeutics.

Language: Английский

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Pan-cancer analysis identifies EIPR1 as a potential prognostic and immunological biomarker for lung adenocarcinoma and its functional validation

Gene, Journal Year: 2025, Volume and Issue: unknown, P. 149439 - 149439

Published: March 1, 2025

Language: Английский

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