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A druggable redox switch on SHP1 controls macrophage inflammation

ABSTRACT: Immunological proteins are major disease targets and the majority remain undrugged. Post-translational redox modification of protein cysteine residues has emerged as a mode of immune cell regulation, especially in the context of the macrophage cytokine response.1 Here, we develop a strategy for systematic discovery and small molecule functionalization of redox-regulated cysteines on immunological proteins. Using deep redox proteomics, we annotate 788 cysteines across diverse functional domains of immune-relevant proteins that are redox regulated in vivo. We demonstrate how these sites can be exploited to develop cysteine-directed pharmacology, exemplified by a newfound cysteine activation site on the core immunological regulator SHP1. By targeting Cys102 on SHP1, we develop a highly selective covalent SHP1 agonist, SCA. SCA binding to Cys102 in the N-terminal Src Homology 2 (N-SH2) domain promotes its rearrangement to relieve auto-inhibition and drive SHP1 activation. In macrophages and in vivo, SCA and its analogues rapidly and selectively engage SHP1 Cys102 and antagonize IL-1 Receptor-Associated Kinase signaling, pro-inflammatory cytokine production, and lipopolysaccharide (LPS)-induced sepsis in mice. Together, we discover a druggable cysteine redox switch controlling the macrophage cytokine response and provide a compendium of functionally annotated redox regulated sites for cysteine-directed therapeutics development.

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ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Thomas Wales

LAB HEAD: Thomas E Wales

PROVIDER: PXD055006 | Pride | 2026-02-24

REPOSITORIES: Pride

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Project description:Src family kinases are often overexpressed and constitutively active in cancer cells, where they represent promising targets for therapeutic intervention. In myeloid hematopoietic cells, Hck, Lyn, and Fgr are associated with both chronic and acute forms of myeloid leukemia. All three of these kinases are expressed in acute myeloid leukemia (AML), where high-level expression correlates with poor survival. The pyrrolopyrimidine Src-family kinase inhibitor A-419259 (also known as RK-20449) has been shown to significantly inhibit patient-derived AML bone marrow cell growth in immunocompromised mice. Recent work has identified an N-phenylbenzamide kinase inhibitor, known as TL02-59, which potently inhibited Fgr kinase activity in vitro and reversed orthotopic engraftment of AML cells in the bone marrow and spleen of immunocompromised mice following oral administration. The inhibitory mechanism of this compound with Fgr or other Src-family members has not been reported. Both wild-type Fgr and a tail mutant (i.e., replacement of Tyr527 with Phe) were shown to produce equal numbers of transformed colonies when expressed in rodent fibroblasts, whereas wild-type Hck transforming activity was completely repressed. In both Hck and Fgr, however, the tail tyrosine residue was shown to be phosphorylated, and hydrogen deuterium exchange mass spectrometry (HDX MS) of near-full-length Fgr was consistent with the closed conformation in solution, with the SH3 domain bound to the SH2-kinase linker and the tail bound to SH2. Here we present the first X-ray crystal structures of near-full-length Fgr bound to the ATP site inhibitors A-419259 and TL02-59. Structural changes induced by the inhibitors in the crystalline state were validated in solution using HDX MS, with A-419259 stabilizing the closed conformation and TL02-59 enhancing exposure of the SH3 domain to solvent. These new structures help to explain the constitutive activity of wild-type Fgr in cells as well as its unique sensitivity to TL02-59, which is currently in development for AML and other maladies.

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	1_SHP1_10m_1.raw.zip	Raw
	1_SHP1_10m_2.raw.zip	Raw
	1_SHP1_10m_3.raw.zip	Raw
	1_SHP1_10m_4.raw.zip	Raw
	1_SHP1_10s_1.raw.zip	Raw

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A druggable redox switch on SHP1 controls macrophage inflammation

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