RESUMO
AXL is a receptor tyrosine kinase that plays a key role in tumor growth and proliferation. The scientific community has validated AXL as therapeutic target in the treatment of cancers for several years now, and several AXL inhibitors have been developed but none of them are approved. In this context, we started to design new kinase inhibitors targeting AXL from the 7-azaindole scaffold well known to interact with the ATP binding site of the kinase. Focused screening and chemical diversification around 7-azaindole scaffold were developed, based on modeling studies and medicinal chemistry rational, leading to the discovery of a new family of hits with potent inhibitory activity against AXL.
Assuntos
Indóis/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Tirosina Quinase AxlRESUMO
A series of benzene sulfonamides incorporating thio, sulfinyl or sulfonyl glycoside moieties were synthesized. These glycoconjugates were investigated for their ability to inhibit the enzymatic activity of four human carbonic anhydrases (hCA): isozymes I, II and tumour-associated isozymes IX and XII. The oxidation state of the sulfur in the carbohydrate tail moiety did not influence either enzyme inhibition potency or isozyme selectivity even though presenting opportunities for differing interactions with the target isozymes.
Assuntos
Benzeno/química , Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/metabolismo , Galactosídeos/farmacologia , Glicoconjugados/síntese química , Glicoconjugados/farmacologia , Sulfonamidas/farmacologia , Benzeno/metabolismo , Inibidores da Anidrase Carbônica/metabolismo , Galactosídeos/síntese química , Galactosídeos/metabolismo , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/metabolismoRESUMO
Efforts were made to improve a series of potent dual ABL/SRC inhibitors based on a 7-azaindole core with the aim of developing compounds that demonstrate a wider activity on selected oncogenic kinases. Multi-targeted kinase inhibitors (MTKIs) were then derived, focusing on kinases involved in both angiogenesis and tumorigenesis processes. Antiproliferative activity studies using different cellular models led to the discovery of a lead candidate (6z) that combined both antiangiogenic and antitumoral effects. The activity of 6z was assessed against a panel of kinases and cell lines including solid cancers and leukemia cell models to explore its potential therapeutic applications. With its potency and selectivity for oncogenic kinases, 6z was revealed to be a focused MTKI that should have a bright future in fighting a wide range of cancers.