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1.
Commun Biol ; 5(1): 571, 2022 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-35681099

RESUMO

Ribonucleotide reductase (RNR) is composed of two non-identical subunits, R1 and R2, and plays a crucial role in balancing the cellular dNTP pool, establishing it as an attractive cancer target. Herein, we report the discovery of a highly potent and selective small-molecule inhibitor, TAS1553, targeting protein-protein interaction between R1 and R2. TAS1553 is also expected to demonstrate superior selectivity because it does not directly target free radical or a substrate binding site. TAS1553 has shown antiproliferative activity in human cancer cell lines, dramatically reducing the intracellular dATP pool and causing DNA replication stress. Furthermore, we identified SLFN11 as a biomarker that predicts the cytotoxic effect of TAS1553. Oral administration of TAS1553 demonstrated robust antitumor efficacy against both hematological and solid cancer xenograft tumors and also provided a significant survival benefit in an acute myelogenous leukemia model. Our findings strongly support the evaluation of TAS1553 in clinical trials.


Assuntos
Antineoplásicos , Inibidores Enzimáticos , Ribonucleotídeo Redutases , Animais , Antineoplásicos/farmacologia , Replicação do DNA , Inibidores Enzimáticos/farmacologia , Humanos , Proteínas Nucleares/metabolismo , Ribonucleotídeo Redutases/antagonistas & inibidores
2.
Elife ; 62017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28264193

RESUMO

The target of rapamycin (TOR) protein kinase forms multi-subunit TOR complex 1 (TORC1) and TOR complex 2 (TORC2), which exhibit distinct substrate specificities. Sin1 is one of the TORC2-specific subunit essential for phosphorylation and activation of certain AGC-family kinases. Here, we show that Sin1 is dispensable for the catalytic activity of TORC2, but its conserved region in the middle (Sin1CRIM) forms a discrete domain that specifically binds the TORC2 substrate kinases. Sin1CRIM fused to a different TORC2 subunit can recruit the TORC2 substrate Gad8 for phosphorylation even in the sin1 null mutant of fission yeast. The solution structure of Sin1CRIM shows a ubiquitin-like fold with a characteristic acidic loop, which is essential for interaction with the TORC2 substrates. The specific substrate-recognition function is conserved in human Sin1CRIM, which may represent a potential target for novel anticancer drugs that prevent activation of the mTORC2 substrates such as AKT.


Assuntos
Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteínas de Schizosaccharomyces pombe/química , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Transporte/genética , Sequência Conservada , Células HEK293 , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Dobramento de Proteína , Mapeamento de Interação de Proteínas , Schizosaccharomyces/enzimologia , Proteínas de Schizosaccharomyces pombe/genética , Especificidade por Substrato
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