Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold

Autor(es):Mostrar menos -

Serafim, Ricardo A. M. ^{[1, 2]} ; Sorrell, Fiona J. ^[3] ; Berger, Benedict-Tilman ^{[4, 5]} ; Collins, Ross J. ^[6] ; Vasconcelos, Stanley N. S. ^{[1, 2]} ; Massirer, Katlin B. ^{[1, 2]} ; Knapp, Stefan ^{[4, 5]} ; Bennett, James ^[3] ; Fedorov, Oleg ^[3] ; Patel, Hitesh ^[6] ; Zuercher, William J. ^[7] ; Elkins, Jonathan M. ^{[1, 3]}

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, UNICAMP, Struct Genom Consortium, BR-13083886 Campinas, SP - Brazil

^[2] Univ Campinas UNICAMP, Ctr Med Chem CQMED, Ctr Mol Biol & Genet Engn CBMEG, BR-13083875 Campinas, SP - Brazil

^[3] Univ Oxford, Ctr Med Discovery, Oxford OX3 7DQ - England

^[4] Goethe Univ Frankfurt, Inst Pharmaceut Chem, D-60438 Frankfurt - Germany

^[5] Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci, Struct Genom Consortium, D-60438 Frankfurt - Germany

^[6] Cardiff Univ, Sch Biosci, Med Discovery Inst, Cardiff CF10 3AT - Wales

^[7] Univ N Carolina, Struct Genom Consortium, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 - USA

• Tipo de documento: Artigo Científico
• Fonte: Journal of Medicinal Chemistry; v. 64, n. 18, p. 13259-13278, SEP 23 2021.
• Citações Web of Science: 0

Resumo

SLK (STE20-like kinase) and STK10 (serine/threonine kinase 10) are closely related kinases whose enzymatic activity is linked to the regulation of ezrin, radixin, and moesin function and to the regulation of lymphocyte migration and the cell cycle. We identified a series of 3-anilino-4-arylmaleimides as dual inhibitors of SLK and STK10 with good kinome-wide selectivity. Optimization of this series led to multiple SLK/STK10 inhibitors with nanomolar potency. Crystal structures of exemplar inhibitors bound to SLK and STK10 demonstrated the binding mode of the inhibitors and rationalized their selectivity. Cellular target engagement assays demonstrated the binding of the inhibitors to SLK and STK10 in cells. Further selectivity analyses, including analysis of activity of the reported inhibitors against off-targets in cells, identified compound 31 as the most potent and selective inhibitor of SLK and STK10 yet reported. (AU)

• Processo FAPESP: 18/09475-5 - Novas abordagens para inibidores de proteínas quinases MRCKa, MRCKb E MRCKg
• Beneficiário: Stanley Nunes Siqueira Vasconcelos
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/25320-6 - Planejamento e síntese de inibidores para proteínas quinases subexploradas relacionadas com RNA e epigenética
• Beneficiário: Ricardo Augusto Massarico Serafim
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado