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1.
Science ; 378(6624): 1097-1104, 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36480603

RESUMO

The search for cell-permeable drugs has conventionally focused on low-molecular weight (MW), nonpolar, rigid chemical structures. However, emerging therapeutic strategies break traditional drug design rules by employing flexibly linked chemical entities composed of more than one ligand. Using complementary genome-scale chemical-genetic approaches we identified an endogenous chemical uptake pathway involving interferon-induced transmembrane proteins (IFITMs) that modulates the cell permeability of a prototypical biopic inhibitor of MTOR (RapaLink-1, MW: 1784 g/mol). We devised additional linked inhibitors targeting BCR-ABL1 (DasatiLink-1, MW: 1518 g/mol) and EIF4A1 (BisRoc-1, MW: 1466 g/mol), uptake of which was facilitated by IFITMs. We also found that IFITMs moderately assisted some proteolysis-targeting chimeras and examined the physicochemical requirements for involvement of this uptake pathway.

2.
Nat Chem Biol ; 18(9): 934-941, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35590003

RESUMO

The expansion of the target landscape of covalent inhibitors requires the engagement of nucleophiles beyond cysteine. Although the conserved catalytic lysine in protein kinases is an attractive candidate for a covalent approach, selectivity remains an obvious challenge. Moreover, few covalent inhibitors have been shown to engage the kinase catalytic lysine in animals. We hypothesized that reversible, lysine-targeted inhibitors could provide sustained kinase engagement in vivo, with selectivity driven in part by differences in residence time. By strategically linking benzaldehydes to a promiscuous kinase binding scaffold, we developed chemoproteomic probes that reversibly and covalently engage >200 protein kinases in cells and mice. Probe-kinase residence time was dramatically enhanced by a hydroxyl group ortho to the aldehyde. Remarkably, only a few kinases, including Aurora A, showed sustained, quasi-irreversible occupancy in vivo, the structural basis for which was revealed by X-ray crystallography. We anticipate broad application of salicylaldehyde-based probes to proteins that lack a druggable cysteine.


Assuntos
Lisina , Inibidores de Proteínas Quinases , Animais , Cisteína/metabolismo , Lisina/metabolismo , Camundongos , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo
3.
J Am Chem Soc ; 142(11): 4960-4964, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32105459

RESUMO

Eukaryotic translation initiation factor 4E (eIF4E) binds the m7GTP cap structure at the 5'-end of mRNAs, stimulating the translation of proteins implicated in cancer cell growth and metastasis. eIF4E is a notoriously challenging target, and most of the reported inhibitors are negatively charged guanine analogues with negligible cell permeability. To overcome these challenges, we envisioned a covalent targeting strategy. As there are no cysteines near the eIF4E cap binding site, we developed a covalent docking approach focused on lysine. Taking advantage of a "make-on-demand" virtual library, we used covalent docking to identify arylsulfonyl fluorides that target a noncatalytic lysine (Lys162) in eIF4E. Guided by cocrystal structures, we elaborated arylsulfonyl fluoride 2 to 12, which to our knowledge is the first covalent eIF4E inhibitor with cellular activity. In addition to providing a new tool for acutely inactivating eIF4E in cells, our computational approach may offer a general strategy for developing selective lysine-targeted covalent ligands.


Assuntos
Fator de Iniciação 4E em Eucariotos/antagonistas & inibidores , Lisina/química , Sulfonamidas/farmacologia , Sítios de Ligação , Descoberta de Drogas , Fator de Iniciação 4E em Eucariotos/química , Fator de Iniciação 4E em Eucariotos/metabolismo , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Sulfonamidas/metabolismo
4.
Elife ; 32014 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-25369635

RESUMO

Posttranslational modifications (PTMs) play a crucial role in a wide range of biological processes. Lysine crotonylation (Kcr) is a newly discovered histone PTM that is enriched at active gene promoters and potential enhancers in mammalian cell genomes. However, the cellular enzymes that regulate the addition and removal of Kcr are unknown, which has hindered further investigation of its cellular functions. Here we used a chemical proteomics approach to comprehensively profile 'eraser' enzymes that recognize a lysine-4 crotonylated histone H3 (H3K4Cr) mark. We found that Sirt1, Sirt2, and Sirt3 can catalyze the hydrolysis of lysine crotonylated histone peptides and proteins. More importantly, Sirt3 functions as a decrotonylase to regulate histone Kcr dynamics and gene transcription in living cells. This discovery not only opens opportunities for examining the physiological significance of histone Kcr, but also helps to unravel the unknown cellular mechanisms controlled by Sirt3, that have previously been considered solely as a deacetylase.


Assuntos
Crotonatos/metabolismo , Genoma Humano , Histonas/metabolismo , Processamento de Proteína Pós-Traducional , Sirtuína 1/metabolismo , Sirtuína 2/metabolismo , Sirtuína 3/metabolismo , Biotina/química , Química Click , Crotonatos/química , Células HEK293 , Células HeLa , Histonas/química , Histonas/genética , Humanos , Hidrólise , Marcação por Isótopo , Lisina/química , Lisina/metabolismo , Modelos Moleculares , Peptídeos/síntese química , Peptídeos/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Proteômica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sirtuína 1/química , Sirtuína 1/genética , Sirtuína 2/química , Sirtuína 2/genética , Sirtuína 3/química , Sirtuína 3/genética , Estreptavidina/química
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