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1.
Eur J Med Chem ; 247: 115035, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36603507

RESUMO

Influenza is one of the leading causes of disease-related mortalities worldwide. Several strategies have been implemented during the past decades to hinder the replication cycle of influenza viruses, all of which have resulted in the emergence of resistant virus strains. The most recent example is baloxavir marboxil, where a single mutation in the active site of the target endonuclease domain of the RNA-dependent-RNA polymerase renders the recent FDA approved compound ∼1000-fold less effective. Raltegravir is a first-in-class HIV inhibitor that shows modest activity to the endonuclease. Here, we have used structure-guided approaches to create rationally designed derivative molecules that efficiently engage the endonuclease active site. The design strategy was driven by our previously published structures of endonuclease-substrate complexes, which allowed us to target functionally conserved residues and reduce the likelihood of resistance mutations. We succeeded in developing low nanomolar equipotent inhibitors of both wild-type and baloxavir-resistant endonuclease. We also developed macrocyclic versions of these inhibitors that engage the active site in the same manner as their 'open' counterparts but with reduced affinity. Structural analyses provide clear avenues for how to increase the affinity of these cyclic compounds.


Assuntos
Dibenzotiepinas , Inibidores de Integrase de HIV , Influenza Humana , Orthomyxoviridae , Humanos , RNA Polimerase Dependente de RNA , Piridonas/farmacologia , Piridonas/uso terapêutico , Influenza Humana/tratamento farmacológico , Dibenzotiepinas/farmacologia , Dibenzotiepinas/uso terapêutico , Endonucleases , Triazinas/farmacologia , Antivirais/farmacologia
2.
J Med Chem ; 64(11): 7296-7311, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34042448

RESUMO

Whereas the PROTAC approach to target protein degradation greatly benefits from rational design, the discovery of small-molecule degraders relies mostly on phenotypic screening and retrospective target identification efforts. Here, we describe the design, synthesis, and screening of a large diverse library of thalidomide analogues against a panel of patient-derived leukemia and medulloblastoma cell lines. These efforts led to the discovery of potent and novel GSPT1/2 degraders displaying selectivity over classical IMiD neosubstrates, such as IKZF1/3, and high oral bioavailability in mice. Taken together, this study offers compound 6 (SJ6986) as a valuable chemical probe for studying the role of GSPT1/2 in vitro and in vivo, and it supports the utility of a diverse library of CRBN binders in the pursuit of targeting undruggable oncoproteins.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , Fatores de Terminação de Peptídeos/metabolismo , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Ubiquitina-Proteína Ligases/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Administração Oral , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Meia-Vida , Humanos , Fator de Transcrição Ikaros/metabolismo , Camundongos , Simulação de Dinâmica Molecular , Estudos Retrospectivos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Relação Estrutura-Atividade , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Talidomida/metabolismo , Talidomida/farmacologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
3.
Cancer Res ; 80(17): 3507-3518, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32651255

RESUMO

Inhibition of members of the bromodomain and extraterminal (BET) family of proteins has proven a valid strategy for cancer chemotherapy. All BET identified to date contain two bromodomains (BD; BD1 and BD2) that are necessary for recognition of acetylated lysine residues in the N-terminal regions of histones. Chemical matter that targets BET (BETi) also interact via these domains. Molecular and cellular data indicate that BD1 and BD2 have different biological roles depending upon their cellular context, with BD2 particularly associated with cancer. We have therefore pursued the development of BD2-selective molecules both as chemical probes and as potential leads for drug development. Here we report the structure-based generation of a novel series of tetrahydroquinoline analogs that exhibit >50-fold selectivity for BD2 versus BD1. This selective targeting resulted in engagement with BD-containing proteins in cells, resulting in modulation of MYC proteins and downstream targets. These compounds were potent cytotoxins toward numerous pediatric cancer cell lines and were minimally toxic to nontumorigenic cells. In addition, unlike the pan BETi (+)-JQ1, these BD2-selective inhibitors demonstrated no rebound expression effects. Finally, we report a pharmacokinetic-optimized, metabolically stable derivative that induced growth delay in a neuroblastoma xenograft model with minimal toxicity. We conclude that BD2-selective agents are valid candidates for antitumor drug design for pediatric malignancies driven by the MYC oncogene. SIGNIFICANCE: This study presents bromodomain-selective BET inhibitors that act as antitumor agents and demonstrates that these molecules have in vivo activity towards neuroblastoma, with essentially no toxicity.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Neoplasias , Fatores de Transcrição/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Criança , Feminino , Humanos , Camundongos , Camundongos SCID , Neoplasias/genética , Neoplasias/metabolismo , Domínios Proteicos , Proteínas Proto-Oncogênicas c-myc/genética , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Bioorg Med Chem Lett ; 21(15): 4592-6, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21708465

RESUMO

We report the synthesis of a pyrimidinone library that targets anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase. This library was generated in three steps from a versatile commercially available starting material. Some compounds within this library showed single digit micromolar inhibition of ALK in vitro, while showing minimal inhibition of other homologous insulin receptor family kinases including the human insulin receptor kinase (IRK), at the highest concentrations investigated. We also present initial ALK structure-activity relationships for this library.


Assuntos
Inibidores de Proteínas Quinases/síntese química , Pirimidinonas/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Quinase do Linfoma Anaplásico , Antígenos CD/metabolismo , Humanos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Receptor de Insulina/antagonistas & inibidores , Receptor de Insulina/metabolismo , Relação Estrutura-Atividade
5.
J Med Chem ; 53(24): 8709-15, 2010 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-21105730

RESUMO

Inhibition of intestinal carboxylesterases may allow modification of the pharmacokinetics/pharmacodynamic profile of existing drugs by altering half-life or toxicity. Since previously identified diarylethane-1,2-dione inhibitors are decidedly hydrophobic, a modified dione scaffold was designed and elaborated into a >300 member library, which was subsequently screened to establish the SAR for esterase inhibition. This allowed the identification of single digit nanomolar hiCE inhibitors that showed improvement in selectivity and measured solubility.


Assuntos
Carboxilesterase/antagonistas & inibidores , Inibidores da Colinesterase/síntese química , Glioxal/análogos & derivados , Glioxal/síntese química , Piridinas/síntese química , Acetilcolinesterase/química , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Glioxal/química , Humanos , Piridinas/química , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade
7.
ACS Med Chem Lett ; 1(9): 460-465, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-21243104

RESUMO

A library of diarylurea IGFR inhibitors was screened for activity against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. The 4-aminoquinaldine-derived diarylureas displayed promising antimalarial potency. Further exploration of the B ring of 4-aminoquinaldinyl ureas allowed identification of several quinaldin-4-yl ureas 4{13, 39} and 4{13, 58} sufficiently potent against both 3D7 and K1 strains to qualify as bone fide leads.

8.
J Comb Chem ; 11(6): 1100-4, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19754047

RESUMO

To identify novel potentially broad spectrum antiviral compounds against RNA viruses, we have developed the parallel synthesis of a structurally interesting class of 2-substituted-4,5-dihydroxypyrimidine-6-carboxamides. Variously 2-substituted-4,5-dihydroxypyrimidine-6-carboxylate methyl esters were initially prepared and were then diversified via a facile amidation reaction. This strategy affords libraries of thousands of diverse drug-like compounds for screening. Biological evaluation of a set of these compounds, via a small initial screen, identified antiviral compounds against a representative RNA virus (Sendai virus, a paramyxovirus). We provide details on the synthetic protocols and the in vitro antiviral activity studies, as part of our initial investigation of the resulting targeted libraries.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Técnicas de Química Combinatória/métodos , Pirimidinas/química , Pirimidinas/farmacologia , Vírus Sendai/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Antivirais/química , Avaliação Pré-Clínica de Medicamentos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Estereoisomerismo
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