9f32
Crystal structure of ULK1 with a covalent compound GCL 99
Structural highlights
FunctionULK1_HUMAN Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK and also acts as a regulator of AMPK by mediating phosphorylation of AMPK subunits PRKAA1, PRKAB2 and PRKAG1, leading to negatively regulate AMPK activity. May phosphorylate ATG13/KIAA0652 and RPTOR; however such data need additional evidences. Plays a role early in neuronal differentiation and is required for granule cell axon formation.[1] [2] [3] Publication Abstract from PubMedProtein kinases are important drug targets, yet specific inhibitors have been developed for only a fraction of the more than 500 human kinases. A major challenge in designing inhibitors for highly related kinases is selectivity. Unlike their non-covalent counterparts, covalent inhibitors offer the advantage of selectively targeting structurally similar kinases by modifying specific protein side chains, particularly non-conserved cysteines. Previously, covalent fragment screens yielded potent and selective compounds for individual kinases such as ERK1/2 but have not been applied to the broader kinome. Furthermore, many of the accessible cysteine positions have not been addressed so far. Here, we outline a generalizable approach to sample ATP-site cysteines with fragment-like covalent inhibitors. We present the development of a kinase-focused fragment library and its systematic screening against a curated selection of 47 kinases, with 60 active site-proximal cysteines using LC/MS and differential scanning fluorimetry (DSF) assays, followed by hit validation through various complementary techniques. Our findings expand the repertoire of targetable cysteines within protein kinases, provide insight into unique binding modes identified from crystal structures and deliver isoform-specific hits with promising profiles as starting points for the development of highly potent and selective covalent inhibitors. Probing the Protein Kinases' Cysteinome by Covalent Fragments.,Wang G, Seidler NJ, Rohm S, Pan Y, Liang XJ, Haarer L, Berger BT, Sivashanmugam SA, Wydra VR, Forster M, Laufer SA, Chaikuad A, Gehringer M, Knapp S Angew Chem Int Ed Engl. 2024 Dec 24:e202419736. doi: 10.1002/anie.202419736. PMID:39716901[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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