RESUMO
The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2. Structure-guided optimization, including several computational methods, led to the discovery of two structurally distinct series of SHP2 inhibitors binding to the previously reported allosteric tunnel binding site (Tunnel Site). One of these series was advanced to a low-nanomolar lead that inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts. Furthermore, a third series of SHP2 inhibitors was discovered binding to a previously unreported site, lying at the interface of the C-terminal SH2 and catalytic domains.
Assuntos
Neoplasias , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Humanos , Camundongos , Animais , Transdução de Sinais , Receptores Proteína Tirosina Quinases/metabolismo , Sítio AlostéricoRESUMO
Here we report a highly conserved new binding site located at the interface between the protease and helicase domains of the hepatitis C virus (HCV) NS3 protein. Using a chemical lead, identified by fragment screening and structure-guided design, we demonstrate that this site has a regulatory function on the protease activity via an allosteric mechanism. We propose that compounds binding at this allosteric site inhibit the function of the NS3 protein by stabilizing an inactive conformation and thus represent a new class of direct-acting antiviral agents.
Assuntos
Sítio Alostérico , Proteínas não Estruturais Virais/metabolismo , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/efeitos dos fármacos , Sítio Alostérico/genética , Antivirais/química , Antivirais/farmacologia , Relação Dose-Resposta a Droga , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/efeitos dos fármacos , Proteínas não Estruturais Virais/genéticaRESUMO
Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.
RESUMO
[reaction: see text] A synthesis of 28, the carbon framework of the eleutherobin aglycone, is reported in a 15-step sequence from readily available starting materials. The tandem Diels-Alder reaction of 6 and 7 to produce 18, in which three new rings and six new stereocenters are formed, is a key step in the reaction sequence.
